CBL mutations in chronic myelomonocytic leukemia often occur in the RING domain with multiple subclones per patient: Implications for targeting.

Chronic myelomonocytic leukemia (CMML) is a rare blood cancer of older adults (3 in every 1,000,000 persons) characterized by poor survival and lacking effective mutation-specific therapy. Mutations in the ubiquitin ligase Cbl occur frequently in CMML and share biological and molecular features with a clonal disease occurring in children, juvenile myelomonocytic leukemia (JMML). Here we analyzed the clinical presentations, molecular features and immunophenotype of CMML patients with CBL mutations enrolled in a prospective Phase II clinical trial stratified according to molecular markers. Clinically, CBL mutations were associated with increased bone marrow blasts at diagnosis, leukocytosis and splenomegaly, similar to patients harboring NRAS or KRAS mutations. Interestingly, 64% of patients presented with more than one CBL variant implying a complex subclonal architecture, often with co-occurrence of TET2 mutations. We found CBL mutations in CMML frequently clustered in the RING domain in contrast to JMML, where mutations frequently involve the linker helix region (P<0.0001). According to our comparative alignment of available X-ray structures, mutations in the linker helix region such as Y371E give rise to conformational differences that could be exploited by targeted therapy approaches. Furthermore, we noted an increased percentage of CMML CD34+ stem and progenitor cells expressing CD116 and CD131 in all CBL mutant cases and increased CD116 receptor density compared to healthy controls, similar to CMML overall. In summary, our data demonstrate that CBL mutations are associated with distinct molecular and clinical features in CMML and are potentially targetable with CD116-directed immunotherapy.

2D to 3D Magnetism in Synthetic Micas.

Fe-based mica minerals usually display two opposing magnetic ground states, either they behave as spin-glasses or as layered ferrimagnets. No definite reason has been proposed as an explanation for this duality. This conundrum is unraveled by comparing the synthetic micas KFe3[MGe3]O10X2 with M═Fe and Ga, X═OH- and F-. Neutron diffraction demonstrates a 2D to 3D magnetic transition in KFe3[FeGe3]O10(OH)2 while just hints or no order at all are observed for the fluorides with M═Fe and Ga respectively. The 3D transition is triggered by the presence of iron in the intralayer tetrahedra. DFT+U calculations show that the magnetic exchange couplings between the previously believed solely magnetic octahedral layers would otherwise be frustrated without this intralayer iron.

Antipolar 2D Metallicity with Tunable Valence Wx+ (5 ≤ x ≤ 5.6) in the Layered Monophosphate Tungsten Bronzes [Ba(PO4)2]WmO3m-3.

The newly discovered series of layered monophosphate tungsten bronzes (L-MPTB) [Ba(PO4)2]WmO3m-3 consist of m-layer-thick slabs of WO6 octahedra separated by barium-phosphate spacers. They display a 2D metallic behavior confined in the central part of the perovskite slabs. Here, we report the missing m = 2 member of this series, containing the rather uncommon W5+ oxidation state. We have analyzed its structure-property relationships in relation to the other members of the L-MPTB family. In particular, we have determined its crystal structure by means of single-crystal X-ray and electron diffraction and investigated its physical properties from resistivity, Seebeck-coefficient and heat-capacity measurements combined with first-principles calculations. All the L-MPTB compounds show metallic behavior down to 1.8 K without any clear charge-density-wave (CDW) order. The m = 2 member, however, displays an increased influence of the spacer that translates into anisotropic negative thermal expansion, reversed thermopower and reversed crystal-field splitting of the tungsten t2g orbitals. Our analysis of the full [Ba(PO4)2]WmO3m-3 series reveals a systematic and significant W off-centering in their octahedral coordination. We identify the resulting anti-polar character of these W displacements as the crucial aspect behind the 2D metallicity of these systems: It leads to the presence of bound charges whose screening determines the distribution of mobile charges, tending to accumulate at the center of the [WmO3-m] block. We argue that this mechanism is analogous to enhanced conductivity observed for charged domain walls in ferroelectrics, thus providing a general design rule to promote 2D metallicity in layered systems.

Metal concentrations and KIM-1 levels in school-aged children: a cross-sectional study.

Environmental exposure to heavy metals and metalloids, originating from sources such as mining and manufacturing activities, has been linked to adverse renal effects. This cross-sectional study assessed children's exposure to these elements and its association with urinary kidney injury molecule-1 (KIM-1). We analyzed data from 99 school-aged children residing in nine localities within the state of Colima, Mexico, during the latter half of 2023. Levels of 23 metals/metalloids and urinary KIM-1 were measured using inductively coupled plasma mass spectrometry (ICP-MS) and enzyme-linked immunosorbent assay, respectively. Detectable levels of these contaminants were found in over 91% of participants, with varied exposure profiles observed across locations ( p = 0.019). After adjusting for confounding factors like gender, age, and locality, higher levels of six metals/metalloids (boron, cadmium, cesium, lithium, selenium, zinc) were significantly associated with increased KIM-1 levels. Tailored mitigation efforts are crucial to protect children from regional pollutant burdens. However, limitations exist, as our study did not capture all potential factors influencing heavy metal/metalloid and KIM-1 levels.

Development of a Smartwatch with Gas and Environmental Sensors for Air Quality Monitoring.

In recent years, there has been a growing interest in developing portable and personal devices for measuring air quality and surrounding pollutants, partly due to the need for ventilation in the aftermath of COVID-19 situation. Moreover, the monitoring of hazardous chemical agents is a focus for ensuring compliance with safety standards and is an indispensable component in safeguarding human welfare. Air quality measurement is conducted by public institutions with high precision but costly equipment, which requires constant calibration and maintenance by highly qualified personnel for its proper operation. Such devices, used as reference stations, have a low spatial resolution since, due to their high cost, they are usually located in a few fixed places in the city or region to be studied. However, they also have a low temporal resolution, providing few samples per hour. To overcome these drawbacks and to provide people with personalized and up-to-date air quality information, a personal device (smartwatch) based on MEMS gas sensors has been developed. The methodology followed to validate the performance of the prototype was as follows: firstly, the detection capability was tested by measuring carbon dioxide and methane at different concentrations, resulting in low detection limits; secondly, several experiments were performed to test the discrimination capability against gases such as toluene, xylene, and ethylbenzene. principal component analysis of the data showed good separation and discrimination between the gases measured.

Exploring Heavy Metal and Metalloid Exposure in Children: A Pilot Biomonitoring Study near a Sugarcane Mill.

Sugarcane production has been linked to the release of heavy metals and metalloids (HM/MTs) into the environment, raising concerns about potential health risks. This study aimed to assess the levels of 19 HM/MTs in children living near a sugarcane mill through a pilot biomonitoring investigation. We investigated sex-related differences in these element levels and their correlations. A cross-sectional study was conducted, analyzing data from 20 children in the latter part of 2023. Spearman correlation coefficients with 95% confidence intervals (CIs) were used to assess the relationships between urinary HM/MT levels. Detectable levels of 17 out of the 19 HM/MTs were found across the entire study sample, with arsenic and copper detectable in 95% of the children. Titanium exhibited higher levels in boys compared to girls (p = 0.017). We identified 56 statistically significant correlations, with 51 of them being positive, while the remaining coefficients indicated negative relationships. This study characterized HM/MT levels in school-aged children residing near a sugarcane mill through a pilot biomonitoring investigation. Further research employing larger sample sizes and longitudinal assessments would enhance our understanding of the dynamics and health impacts of HM/MT exposure in this vulnerable population.

Characterization of Quaternary-Ammonium-Based Ionogel Membranes for Application in Proton Exchange Membrane Fuel Cells.

In recent years, the quest to advance fuel cell technologies has intensified, driven by the imperative to reduce reliance on hydrocarbon-derived fuels and mitigate pollutant emissions. Proton exchange membranes are a critical material of fuel cell technologies. The potential of ionic liquid-based polymer inclusion membranes or ionogels for proton exchange membrane fuel cells (PEMFCs) has recently appeared. Thermal stability, SEM-EDX characterization, NMR and IR characterization, thermogravimetric analysis, ion exchange capacity, and water uptake are key properties of these membranes which need to be investigated. In this work, ionogel based on quaternary ammonium salts, such as [N8,8,8,1+][Cl-], [N8,8,8,1+][Br-], and [N8-10,8-10,8-10,1+][Cl-] in various compositions with poly(vinyl chloride) are extensively studied and characterized based on those key properties. The best properties were obtained when a quaternary ammonium cation was combined with a bromide anion. Finally, ionogels are tested in microbial fuel cells. Microbial fuel cells based on the ionogel reach a maximum of 147 mW/m2, which represents 55% of the reference membrane (Nafion 212). These results indicate that we still have the possibility of improvement through the appropriate selection of the cation and anion of the ionic liquid. Overall, the promise of ionogel membranes as a viable alternative in fuel cell applications has been demonstrated.

Assessment of adaptive behavior in people with intellectual disabilities: Design and development of a new test battery.

Background: Adaptive behavior is an important characteristic of people with intellectual disabilities, and it has been associated with a person's performance in social and work contexts. Indeed, adaptive behavior denotes what a person does independently, without help, support, reminders, or prompts. In Peru, available measures of adaptive behavior are commercial; thus, there is a need for an open-access tool to assess the adaptive behavior of people with intellectual disabilities. For this reason, the aim of the study was to design and develop a new Adaptive Behavior Test Battery for people from 13 to 60 years old with intellectual disabilities who have an interest in being part of the economically active population. Methods: A cross-sectional design was defined, starting with a qualitative approach to designing and constructing the item pool for the test battery. Then, quantitative indexes Aiken's V for content validity and Krippendorff's alpha for inter-observer reliability were estimated, resulting in a first version of the three subscales that comprised the test battery. The initial versions were tested on a sample of 566 persons with intellectual disabilities from two regions of Peru: Lima (Coast) and San Martín (Jungle). The internal structure was analyzed under a factor analysis approach, along with internal consistency measures of reliability. Further analyses of invariance regarding gender, region, and age were carried out. Results: Three observer subscales were proposed: Daily living activities (11 items), Instrumental skills (4 items), and Communication (9 items). All subscales showed excellent psychometric properties denoted by the Aiken's V coefficient, Krippendorff's alpha, factor analysis, internal consistency analysis, and invariance analyses. Conclusion: The developed a new Adaptive Behavior Test Battery is a useful tool for the measurement of adaptive behavior and the monitoring of social and labor inclusion programs for people with intellectual disabilities.

Ferromagnetic Mn3+ Sawtooth Chains in A2(Mn2O)(SeO3)3 (A = K, Rb) Quaternary Selenites.

Two quaternary manganese selenites, A2(Mn2O)(SeO3)3 (A = K, Rb), have been synthesized by hydrothermal reactions. They both crystallize in a complex triclinic (P-1) structure built of Jahn-Teller (JT) distorted Mn3+O4+2 octahedra, connected into nearly isosceles [Mn3O14] triangles, themselves arranged into so-called "sawtooth (ST) chains". The K and Rb compounds show subtle variations in the orientations of the MnO4 planes inside the elementary triangles. The ST chains are structurally and magnetically isolated by SeO3 groups and alkali cations. In the ST chains, predominant ferromagnetic interactions were calculated and verified experimentally, which finally order antiferromagnetically between the chains around TN ≈ 22 K. The spin exchanges calculated by DFT + U and fitted by Monte Carlo simulations allow for the quantification of an effective "overall" model. The specific role of the µ3-O bridge on the ferromagnetic (FM) exchanges is discussed, together with spin reorientations observed in the ordered state. Magnetocrystalline anisotropy along the [110] direction stabilized by ∼50 meV per Mn by spin-orbit coupling (SOC) was found by DFT + U + SOC.

Accelerated Closure of Diabetic Wounds by Efficient Recruitment of Fibroblasts upon Inhibiting a 14-3-3/ROCK Regulatory Axis.

Chronic non-healing wounds negatively impact quality of life and are a significant financial drain on health systems. The risk of infection that exacerbates comorbidities in patients necessitates regular application of wound care. Understanding the mechanisms underlying impaired wound healing are therefore a key priority to inform effective new-generation treatments. In this study, we demonstrate that 14-3-3-mediated suppression of signaling through ROCK is a critical mechanism that inhibits the healing of diabetic wounds. Accordingly, pharmacological inhibition of 14-3-3 by topical application of the sphingo-mimetic drug RB-11 to diabetic wounds on a mouse model of type II diabetes accelerated wound closure more than 2-fold than vehicle control, phenocopying our previous observations in 14-3-3ζ-knockout mice. We also demonstrate that accelerated closure of the wounded epidermis by 14-3-3 inhibition causes enhanced signaling through the Rho-ROCK pathway and that the underlying cellular mechanism involves the efficient recruitment of dermal fibroblasts into the wound and the rapid production of extracellular matrix proteins to re-establish the injured dermis. Our observations that the 14-3-3/ROCK inhibitory axis characterizes impaired wound healing and that its suppression facilitates fibroblast recruitment and accelerated re-epithelialization suggest new possibilities for treating diabetic wounds by pharmacologically targeting this axis.

Elucidating the Mechanism of Metabolism of Cannabichromene by Human Cytochrome P450s.

Cannabichromene (CBC) is a nonpsychoactive phytocannabinoid well-known for its wide-ranging health advantages. However, there is limited knowledge regarding its human metabolism following CBC consumption. This research aimed to explore the metabolic pathways of CBC by various human liver cytochrome P450 (CYP) enzymes and support the outcomes using in vivo data from mice. The results unveiled two principal CBC metabolites generated by CYPs: 8'-hydroxy-CBC and 6',7'-epoxy-CBC, along with a minor quantity of 1″-hydroxy-CBC. Notably, among the examined CYPs, CYP2C9 demonstrated the highest efficiency in producing these metabolites. Moreover, through a molecular dynamics simulation spanning 1 µs, it was observed that CBC attains stability at the active site of CYP2J2 by forming hydrogen bonds with I487 and N379, facilitated by water molecules, which specifically promotes the hydroxy metabolite's formation. Additionally, the presence of cytochrome P450 reductase (CPR) amplified CBC's binding affinity to CYPs, particularly with CYP2C8 and CYP3A4. Furthermore, the metabolites derived from CBC reduced cytokine levels, such as IL6 and NO, by approximately 50% in microglia cells. This investigation offers valuable insights into the biotransformation of CBC, underscoring the physiological importance and the potential significance of these metabolites.

Interleukin-3 production by basal-like breast cancer cells is associated with poor prognosis.

Breast cancer represents a collection of pathologies with different molecular subtypes, histopathology, risk factors, clinical behavior, and responses to treatment. "Basal-like" breast cancers predominantly lack the receptors for estrogen and progesterone (ER/PR), lack amplification of human epidermal growth factor receptor 2 (HER2) but account for 10-15% of all breast cancers, are largely insensitive to targeted treatment and represent a disproportionate number of metastatic cases and deaths. Analysis of interleukin (IL)-3 and the IL-3 receptor subunits (IL-3RA + CSF2RB) reveals elevated expression in predominantly the basal-like group. Further analysis suggests that IL-3 itself, but not the IL-3 receptor subunits, associates with poor patient outcome. Histology on patient-derived xenografts supports the notion that breast cancer cells are a significant source of IL-3 that may promote disease progression. Taken together, these observations suggest that IL-3 may be a useful marker in solid tumors, particularly triple negative breast cancer, and warrants further investigation into its contribution to disease pathogenesis.

Dual inhibition of airway inflammation and fibrosis by common ß cytokine receptor blockade.

BACKGROUND: Patients with severe asthma can present with eosinophilic type 2 (T2), neutrophilic, or mixed inflammation that drives airway remodeling and exacerbations and represents a major treatment challenge. The common ß (ßc) receptor signals for 3 cytokines, GM-CSF, IL-5, and IL-3, which collectively mediate T2 and neutrophilic inflammation. OBJECTIVE: To determine the pathogenesis of ßc receptor-mediated inflammation and remodeling in severe asthma and to investigate ßc antagonism as a therapeutic strategy for mixed granulocytic airway disease. METHODS: ßc gene expression was analyzed in bronchial biopsy specimens from patients with mild-to-moderate and severe asthma. House dust mite extract and Aspergillus fumigatus extract (ASP) models were used to establish asthma-like pathology and airway remodeling in human ßc transgenic mice. Lung tissue gene expression was analyzed by RNA sequencing. The mAb CSL311 targeting the shared cytokine binding site of ßc was used to block ßc signaling. RESULTS: ßc gene expression was increased in patients with severe asthma. CSL311 potently reduced lung neutrophils, eosinophils, and interstitial macrophages and improved airway pathology and lung function in the acute steroid-resistant house dust mite extract model. Chronic intranasal ASP exposure induced airway inflammation and fibrosis and impaired lung function that was inhibited by CSL311. CSL311 normalized the ASP-induced fibrosis-associated extracellular matrix gene expression network and strongly reduced signatures of cellular inflammation in the lung. CONCLUSIONS: ßc cytokines drive steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-ßc antibody CSL311 effectively inhibits mixed T2/neutrophilic inflammation and severe asthma-like pathology and reverses fibrosis gene signatures induced by exposure to commonly encountered environmental allergens.

Metabolomic profile of neuroendocrine tumors identifies methionine, porphyrin, and tryptophan metabolisms as key dysregulated pathways associated with patient survival.

OBJECTIVE: Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways. DESIGN AND METHODS: Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P < .05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA). RESULTS: Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P = .012); 5-year OS of 69.7%, 32.5%, and 27.7% (P = .003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs. CONCLUSIONS: We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients.

Comparative transcriptomic analysis of chemoreceptors in two sympatric scarab beetles, Hylamorpha elegans and Brachysternus prasinus.

Chemoreception through odorant receptors (ORs), ionotropic receptors (IRs) and gustatory receptors (GRs) represents the functions of key proteins in the chemical ecology of insects. Recent studies have identified chemoreceptors in coleopterans, facilitating the evolutionary analysis of not only ORs but also IRs and GRs. Thus, Cerambycidae, Tenebrionidae and Curculionidae have received increased attention. However, knowledge of the chemoreceptors from Scarabaeidae is still limited, particularly for those that are sympatric. Considering the roles of chemoreceptors, this analysis could shed light on evolutionary processes in the context of sympatry. Therefore, the aim of this study was to identify and compare the repertoires of ORs, GRs and IRs between two sympatric scarab beetles, Hylamorpha elegans and Brachysternus prasinus. Here, construction of the antennal transcriptomes of both scarab beetle species and analyses of their phylogeny, molecular evolution and relative expression were performed. Thus, 119 new candidate chemoreceptors were identified for the first time, including 17 transcripts for B. prasinus (1 GR, 3 IRs and 13 ORs) and 102 for H. elegans (22 GRs, 14 IRs and 66 ORs). Orthologs between the two scarab beetle species were found, revealing specific expansions as well as absence in some clades. Purifying selection appears to have occurred on H. elegans and B. prasinus ORs. Further efforts will be focused on target identification to characterize kairomone and/or pheromone receptors.

CoVO3 High-Pressure Polymorphs: To Order or Not to Order?

Materials properties are determined by their compositions and structures. In ABO3 oxides different cation orderings lead to mainly perovskite- or corundum like derivatives with exciting physical properties. Sometimes, a material can be stabilized in more than one structural modification, providing a unique opportunity to explore structure-properties relationship. Here, CoVO3 obtained in both ilmenite-(CoVO3 -I) and LiNbO3 -type (CoVO3 -II) polymorphs at moderate (8-12 GPa) and high pressures (22 GPa), respectively are presented. Their distinctive cation distributions affect drastically the magnetic properties as CoVO3 -II shows a cluster-glass behavior while CoVO3 -I hosts a honeycomb zigzag magnetic structure in the cobalt network. First principles calculations show that the influence of vanadium is crucial for CoVO3 -I, although it is previously considered as non-magnetic in a dimerized spin-singlet state. Contrarily, CoVO3 -II shows two independent interpenetrating antiferromagnetic Co- and ferromagnetic V-hcp sublattices, which intrinsically frustrate any possible magnetic order. CoVO3 -II is also remarkable as the first oxide crystallizing with the LiNbO3 -type structure where both metals contain free d electrons. CoVO3 polymorphs pinpoint therefore as well to a much broader phase field of high-pressure A-site Cobaltites.

Abnormal patterns of sleep and waking behaviors are accompanied by neocortical oscillation disturbances in an Ank3 mouse model of epilepsy-bipolar disorder comorbidity.

ANK3 is a leading bipolar disorder (BD) candidate gene in humans and provides a unique opportunity for studying epilepsy-BD comorbidity. Previous studies showed that deletion of Ank3-1b, a BD-associated variant of Ank3 in mice leads to increased firing threshold and diminished action potential dynamic range of parvalbumin (PV) interneurons and absence epilepsy, thus providing a biological mechanism linking epilepsy and BD. To explore the behavioral overlap of these disorders, we characterized behavioral patterns of Ank3-1b KO mice during overnight home-cage activity and examined network activity during these behaviors using paired video and EEG recordings. Since PV interneurons contribute to the generation of high-frequency gamma oscillations, we anticipated changes in the power of neocortical EEG signals in the gamma frequency range (> 25 Hz) during behavioral states related to human BD symptoms, including abnormal sleep, hyperactivity, and repetitive behaviors. Ank3-1b KO mice exhibited an overall increase in slow gamma (~25-45 Hz) power compared to controls, and slow gamma power correlated with seizure phenotype severity across behaviors. During sleep, increased slow gamma power correlated with decreased time spent in the rapid eye movement (REM) stage of sleep. Seizures were more common during REM sleep compared to non-REM (NREM) sleep. We also found that Ank3-1b KO mice were hyperactive and exhibited a repetitive behavior phenotype that co-occurred with increased slow gamma power. Our results identify a novel EEG biomarker associating Ank3 genetic variation with BD and epilepsy and suggest modulation of gamma oscillations as a potential therapeutic target.

Ferrimagnetic and spin glass behaviour in SrMn2+3Ti4+14M3+4O38 (M = Ti and Fe) synthetic crichtonites.

Novel SrMn3Ti14M4O38 (M = Ti and Fe) compounds with a crichtonite-type structure are reported herein. M = Ti shows a ferrimagnetic behavior at TN = 15 K, while M = Fe creates a ferromagnetic cluster-glass at Tf = 8 K via positional disorder. This family offers a promising magnetic playground.

Multivalued Memory via Freezing of Super-Hard Magnetic Domains in a Quasi 2D-Magnet.

The design of high-density non-volatile memories is a long-standing dream, limited by conventional storage "0" or "1" bits. An alternative paradigm exists in which regions within candidate materials can be magnetized to intermediate values between the saturation limits. In principle, this paves the way to multivalued bits, vastly increasing storage density. Single-molecule magnets, are good examples offering transitions between intramolecular quantum levels, but require ultra-low temperatures and limited relaxation time between magnetization states. It is showed here that the quasi 2D-Ising compound BaFe2 (PO4 )2 overcomes these limitations. The combination of giant magneto-crystalline anisotropy, strong ferromagnetic exchange, and strong intrinsic pinning creates remarkably narrow magnetic domain walls, collectively freezing under Tf ≈15 K. This results in a transition from a soft to a super-hard magnet (coercive force > 14 T). Any magnetization can then be printed and robustly protected from external fields with an energy barrier >9T at 2 K.