Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer's disease.

Asymptomatic Alzheimer's disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer's disease (AD) brain pathology (i.e., beta-amyloid (Aß) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aß, preserving brain health, and slowing AD pathology progression.

Protocol for the isolation and proteomic analysis of pathological tau-seeds.

The aggregation and spreading of "tau-seeds" are key for the development and progression of tauopathies, including Alzheimer's disease. Here we describe the steps to isolate and analyze biochemically active tau-seeds from human, mouse, and cell origin. We detail the procedure to isolate soluble tau-seeds by size exclusion chromatography and seeding assay. The isolated tau-seed can be further analyzed to determine the interactome by mass spectrometry. This workflow identifies protein-protein interactors of tau-seeds, providing a useful tool for finding new therapeutic targets. For complete details on the use and execution of this protocol, please refer to Martinez et al.1.

A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment.

Aging involves the deterioration of organismal function, leading to the emergence of multiple pathologies. Environmental stimuli, including lifestyle, can influence the trajectory of this process and may be used as tools in the pursuit of healthy aging. To evaluate the role of epigenetic mechanisms in this context, we have generated bulk tissue and single cell multi-omic maps of the male mouse dorsal hippocampus in young and old animals exposed to environmental stimulation in the form of enriched environments. We present a molecular atlas of the aging process, highlighting two distinct axes, related to inflammation and to the dysregulation of mRNA metabolism, at the functional RNA and protein level. Additionally, we report the alteration of heterochromatin domains, including the loss of bivalent chromatin and the uncovering of a heterochromatin-switch phenomenon whereby constitutive heterochromatin loss is partially mitigated through gains in facultative heterochromatin. Notably, we observed the multi-omic reversal of a great number of aging-associated alterations in the context of environmental enrichment, which was particularly linked to glial and oligodendrocyte pathways. In conclusion, our work describes the epigenomic landscape of environmental stimulation in the context of aging and reveals how lifestyle intervention can lead to the multi-layered reversal of aging-associated decline.

ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma.

Cancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that, in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-coenzyme A (CoA) synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest (NC) lineage and glucose metabolism genes. Importantly, we show that acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3-dependent manner, providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish melanoma residual disease model, an ALDH1-high subpopulation emerges following BRAF inhibitor treatment, and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma.

Using the Modified Apical Access Technique to Treat Peri-Implant Mucosa Defects: Description of the Technique and Three-Dimensional Quantitative Measurement of Buccal Augmented Tissue.

The importance of augmenting the peri-implant soft- and hard-tissue architecture is now widely accepted. However, while most contemporary research supports this premise, clinicians are encountering peri-implant soft tissue defects with increasing frequency, which they are therefore required to reconstruct. These complications can result from the difficulty of establishing an appropriate diagnosis and treatment plan or from suboptimal clinical situations (implant malposition, insufficient vestibular alveolar bone thickness or inadequate mucosal thickness). In this context, it is the peri-implant soft-tissue phenotype that most influences esthetic and health-related results in the short and long term. This article describes two clinical cases in which a modification of the apical access technique is presented that may be useful in clinical scenarios requiring large gains in mucosal thickness. Use of the modified bilaminar apical access with de-epithelialized free gingival graft technique showed promising results, with a significant increase in mucosal thickness and satisfactory outcomes in esthetics and peri-implant health.

Therapeutic targeting of immunometabolism reveals a critical reliance on hexokinase 2 dosage for microglial activation and Alzheimer's progression.

Neuroinflammation is a prominent feature of Alzheimer's disease (AD). Activated microglia undergo a reprogramming of cellular metabolism necessary to power their cellular activities during disease. Thus, selective targeting of microglial immunometabolism might be of therapeutic benefit for treating AD. In the AD brain, the levels of microglial hexokinase 2 (HK2), an enzyme that supports inflammatory responses by promoting glycolysis, are significantly increased. In addition, HK2 displays non-metabolic activities that extend its inflammatory role beyond glycolysis. The antagonism of HK2 affects microglial phenotypes and disease progression in a gene-dose-dependent manner. HK2 complete loss fails to improve pathology by exacerbating inflammation, while its haploinsufficiency reduces pathology in 5xFAD mice. We propose that the partial antagonism of HK2 is effective in slowing disease progression by modulating NF-κB signaling through its cytosolic target, IKBα. The complete loss of HK2 affects additional inflammatory mechanisms related to mitochondrial dysfunction.

Towards accurate monitoring of water content in woody tissue across tropical forests and other biomes.

Forest ecosystems face increasing drought exposure due to climate change, necessitating accurate measurements of vegetation water content to assess drought stress and tree mortality risks. Although Frequency Domain Reflectometry offers a viable method for monitoring stem water content by measuring dielectric permittivity, challenges arise from uncertainties in sensor calibration linked to wood properties and species variability, impeding its wider usage. We sampled tropical forest trees and palms in eastern Amazônia to evaluate how sensor output differences are controlled by wood density, temperature and taxonomic identity. Three individuals per species were felled and cut into segments within a diverse dataset comprising five dicotyledonous tree and three monocotyledonous palm species on a wide range of wood densities. Water content was estimated gravimetrically for each segment using a temporally explicit wet-up/dry-down approach and the relationship with the dielectric permittivity was examined. Woody tissue density had no significant impact on the calibration, but species identity and temperature significantly affected sensor readings. The temperature artefact was quantitatively important at large temperature differences, which may have led to significant bias of daily and seasonal water content dynamics in previous studies. We established the first tropical tree and palm calibration equation which performed well for estimating water content. Notably, we demonstrated that the sensitivity remained consistent across species, enabling the creation of a simplified one-slope calibration for accurate, species-independent measurements of relative water content. Our one-slope calibration serves as a general, species-independent standard calibration for assessing relative water content in woody tissue, offering a valuable tool for quantifying drought responses and stress in trees and forest ecosystems.

Interdisciplinary innovative approach to an aggressive ossifying fibroma case: Integrating 3D surgery and customized reconstruction in maxillofacial and dental care.

Aggressive ossifying fibroma is a benign fibro-osseous disorder characterized by its aggressive behavior, which complicates its management. In this article, we present a case involving the recurrence of this condition in the maxillary region, with orbital and dental involvement, in a patient who had previously undergone surgery and reconstruction with a microvascularized free fibula flap. A multidisciplinary approach involving maxillofacial surgery and dentistry was employed to deliver a customized and entirely satisfactory solution for the patient. The use of 3D surgery was integral to our approach, encompassing pre-surgical digital planning and the transfer of this planning to the operating room via navigation software. Customized surgical cutting guides facilitated precise resection, while a personalized polyether ether ketone (PEEK) prosthesis was utilized for reconstruction of the malar and infraorbital region. Pre-prosthetic computer-aided design/computer-aided manufacturing (CAD/CAM) surgery, along with dental rehabilitation using transepithelial abutments and dental prostheses on a titanium framework, were employed for dental restoration. During the postoperative period, mobility in the reconstructed maxilla was observed due to the loss of support from the initial reconstruction plate. This was addressed by replacing the plate with a custom-made titanium plate, designed to accommodate the location of the transepithelial abutments and prevent disruption of the dental rehabilitation. This case demonstrates the potential of new technologies when applied within the collaborative framework of maxillofacial surgeons and dentists, enabling effective and definitive solutions in complex reconstruction cases. Key words:Aggressive ossifying fibroma; 3D surgery; customized reconstruction; complex dental reconstruction.

Analyzing the European institutional response to ethical and regulatory challenges of artificial intelligence in addressing discriminatory bias.

The European Union and some of its institutions have taken significant steps to address the challenges posed by the development and use of Artificial Intelligence (AI) in various contexts. The ubiquity of AI applications in everyday life, affecting both citizens and professionals, has made AI a common topic of discussion. However, as is evident from the documents analyzed here, concerns have been raised about the possible negative social consequences of AI, in particular discriminatory bias, making it a particularly relevant issue if people-centred, rights-based AI is to be implemented. This article aims to examine the challenges of defining, identifying and mitigating discriminatory bias in AI systems from two perspectives: (1) to conduct an ethical and normative review of European Commission documents from the last 8 years (from GDPR to AI Act regulation); and (2) to expose recommendations for key stakeholders, including designers, end-users and public authorities, to minimize/mitigate this risk. The document review was carried out on 21 EU regulatory and ethical guidelines in the field of AI, from which 152 measures were extracted, differentiated between design, governance and organizational measures. It has also been observed that there is no clear conceptual framework on the issue at the European level, showing a clear problem in providing definitions of algorithmic bias and discrimination, but not in assessing their potential negative impact on individuals. Secondly, these gaps may affect the concreteness and detail of the possible mitigation/minimization measures proposed and, subsequently, their application in different contexts. Finally, the last section of this paper presents a brief discussion and conclusions on possible issues related to the implementation of the measures extracted and certain limitations of the study.

Single-cell genomics details the maturation block in BCP-ALL and identifies therapeutic vulnerabilities in DUX4-r cases.

B cell progenitor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy, driven by multiple genetic alterations that cause maturation arrest and accumulation of abnormal progenitor B cells. Current treatment protocols with chemotherapy have led to favorable outcomes but are associated with significant toxicity and risk of side effects, highlighting the necessity for highly effective, less toxic, targeted drugs, even in subtypes with a favorable outcome. Here, we used multimodal single-cell sequencing to delineate the transcriptional, epigenetic, and immunophenotypic characteristics of 23 childhood BCP-ALLs, belonging to the BCR::ABL1-positive, ETV6::RUNX1-positive, high hyperdiploid, and recently discovered DUX4-rearranged (DUX4-r) subtypes. Projection of the ALL cells along the normal hematopoietic differentiation axis revealed a diversity in the maturation pattern between the different BCP-ALL subtypes. Whereas the BCR::ABL1-, ETV6::RUNX1-positive, and high hyperdiploidy cells mainly showed similarities to normal pro-B cells, the DUX4-r ALL cells also displayed transcriptional signatures resembling mature B cells. Focusing on the DUX4-r subtype, we found that the blast population displayed multilineage priming toward non-hematopoietic cells, myeloid, and T cell lineages, but also an activation of PI3K/AKT signaling that sensitized the cells to PI3K inhibition in vivo. Given the multilineage priming of the DUX4-r blasts with aberrant expression of the myeloid marker CD371 (CLL-1), we generated chimeric antigen receptor T cells, which effectively eliminated DUX4-r ALL cells in vivo. These results provide a detailed characterization of BCP-ALL at the single-cell level and reveal therapeutic vulnerabilities in the DUX4-r subtype with implications for the understanding of ALL biology and new therapeutic strategies.

GPCR Function in Autophagy Control: A Systematic Approach of Chemical Intervention.

Autophagy facilitates the degradation of cellular content via the lysosome and is involved in cellular homeostasis and stress response pathways. As such, malfunction of autophagy is linked to a variety of diseases ranging from organ-specific illnesses like cardiomyopathy to systemic illnesses such as cancer or metabolic syndromes. Given the variety of autophagic functions within a cell and tissue, regulation of autophagy is complex and contains numerous positive and negative feedback loops. While our knowledge of mechanisms for cargo selectivity has significantly improved over the last decade, our understanding of signaling routes activating individual autophagy pathways remains rather sparse. In this resource study, we report on a well-characterized chemical library containing 77 GPCR-targeting ligands that was used to systematically analyze LC3B-based autophagy as well as ER-phagy flux upon compound treatment. Upon others, compounds TC-G 1004, BAY 60-6583, PSNCBAM-1, TC-G 1008, LPA2 Antagonist 1, ML-154, JTC-801 and ML-290 targeting adenosine receptor A2a (ADORA2A), adenosine receptor A2b (ADORA2B), cannabinoid receptor 1 (CNR1), G-protein coupled receptor 39 (GPR39), lysophosphatidic acid receptor 2 (LPAR2), neuropeptide S receptor 1 (NPSR1), opioid related nociceptin receptor 1 (OPRL1), and relaxin receptor 1 (RXFP1), respectively, were hit compounds for general autophagy flux. From these compounds, only JTC-801 markly increased ER-phagy flux. In addition, the global impact of these selected hit compounds were analyzed by TMT-based mass spectrometry and demonstrated the differential impact of targeting GPCRs on autophagy-associated proteins. This chemical screening exercise indicates to a significant cross-talk between GPCR signaling and regulation of autophagy pathways.

Changes in prenatal cannabis-related diagnosed disorders after the Cannabis Act and the COVID-19 pandemic in Quebec, Canada.

BACKGROUND AND AIMS: Public health concerns regarding pregnant women's health after the enactment of the Cannabis Act in Canada (CAC) (a law that allowed non-medical cannabis use), and the potential impact of the COVID-19 pandemic, call for a contemporary assessment of these two events. Our study measured associations between the CAC, the COVID-19 pandemic and the monthly prevalence rates of cannabis-, all drug- and alcohol-related diagnosed disorders among pregnant women in the province of Quebec. DESIGN, SETTING AND PARTICIPANTS: This was a quasi-experimental design applying an interrupted time-series methodology in the province of Quebec, Canada. The participants were pregnant women aged 15-49 years, between January 2010 and July 2022. MEASUREMENTS: Administrative health data from the Québec Integrated Chronic Disease Surveillance System were used to classify pregnant women according to cannabis-, all drug (excluding cannabis)- and alcohol-related disorders. The CAC (October 2018) and the COVID-19 pandemic (April 2020) were evaluated as (1) slope changes and (2) level changes. Cannabis-, all drug (excluding cannabis)- and alcohol-related disorders were measured by total monthly age-standardized monthly prevalence rate of each disorder for pregnant women aged 15-49 years. FINDINGS: Before the CAC, the prevalence rate of cannabis-related diagnosed disorders significantly increased each month by 0.5% [95% confidence interval (CI) = 0.3-0.6] in the pregnant population. After the CAC, there were significant increases of 24% (95% CI = 1-53) of cannabis-related diagnosed disorders. No significant changes were observed for all drug (excluding cannabis)- and alcohol-related diagnosed disorders associated with the CAC. A non-significant decrease of 20% (95% CI = -38 to 3) was observed during the COVID-19 pandemic in alcohol-related disorders. CONCLUSIONS: The monthly incidence rates of diagnosed cannabis-related disorders in pregnant women in Quebec increased significantly following the enactment of the Cannabis Act in Canada. Diagnoses of all drug (excluding cannabis)- and alcohol-related disorders remained relatively stable.

Natural history of SCLC patients treated in third-line and beyond: A retrospective real world study.

OBJECTIVES: To describe treatment patterns and estimate outcomes among real-world small cell lung cancer (SCLC) patients in the US who received three or more lines of therapy. MATERIALS AND METHODS: We conducted a retrospective analysis of adult patients with SCLC who received a front-line platinum-based regimen and two additional lines of therapy (ie., a cohort of at least three lines of therapy). De-identified patients were selected from a United States Flatiron Health oncology database of electronic health records. Treatment patterns were captured by line of therapy. Outcomes evaluated by line of therapy included real-world overall survival (rwOS), real-world progression free survival (rwPFS), real-world response rate (rwRR) and real-world duration of response (rwDOR). RESULTS: The analysis included 326 3L SCLC patients, of which 103 (32 %) received 4L treatment, and 38 % (39/103) of 4L treated received 5L of therapy. Among the 3L cohort, the average age was 67 years, 49 % were male, and nearly all had a history of smoking (96 %). In the 3L setting, the median rwOS was 5.3 months (95 % Confidence Interval (CI): 4.5, 6.0), median rwPFS was 2.5 months (95 % CI: 2.1, 2.7), rwRR was 19.3 % (95 % CI: 15.2, 24.0) and median DOR was 3.4 months (95 % CI: 2.8, 4.4). No differences were seen in outcomes between the overall cohort and a subgroup of patients treated with front-line platinum-based regimen with an anti-programmed cell death ligand 1 (PD-L1) agent (atezolizumab or durvalumab), in each respective line of therapy. CONCLUSION: Results from this large, real-world study of US patients with SCLC in the 3L setting and beyond highlight the poor treatment outcomes in advanced SCLC patients with existing therapies and underscore the dire need for new therapies for SCLC patients.

Changes in the incidence of cannabis-related disorders after the Cannabis Act and the COVID-19 pandemic in Québec, Canada.

BACKGROUND: The Canadian Cannabis Act (CCA, implemented in October 2018) and the COVID-19 pandemic (April 2020) might have contributed to cannabis-related harms in Québec, known for its stringent cannabis legal framework. We explored changes in incidence rates of cannabis-related disorders (CRD) diagnoses associated with these events in Québec. METHODS: We utilized linked administrative health data to identify individuals aged 15 year+ newly diagnosed with CRD during hospitalizations, emergency, and outpatients clinics across Québec, from January 2010 and March 2022 (147 months). Interrupted time-series analyses (ITSA) assessed differences (as percentage changes) in sex- and age-standardized, and sex-stratified, monthly incidence rates (per 100,000 population) attributed to the CCA and the COVID-19 pandemic, compared to counterfactual scenarios where pre-events trends would continue unchanged. RESULTS: The overall monthly mean rates of incident diagnoses nearly doubled from the pre-CCA period (1.56 per 100,000 population) to the COVID-19 pandemic period (3.02 per 100,000 population). ITSA revealed no statistically significant level or slope changes between adjacent study periods, except for a decrease in the slope of incidence rates among males by 1.84 % (95 % CI -3.41 to -0.24) during the COVID-19 pandemic compared to the post-CCA period. During the post-CCA period, the trends of incidence rates in the general and male populations grew significantly by 1.22 % (95 % CI 0.08 to 2.35) and 1.44 % (0.04 to 2.84) per month, respectively. Similarly significant increases were observed for the general and female populations during the COVID-19 pandemic, with monthly rates rising by 1.43 % (95 % CI 0.75 to 2.12) and 1.75 % (95 % CI 0.13 to 3.37), respectively. These increases more than doubled pre-CCA rates. CONCLUSIONS: The incidence rates of CRD diagnoses across Québec appears to have increased following the implementation of the CCA and during the COVID-19 pandemic. Our findings echo public health concerns regarding potential cannabis-related harms and are consistent with previous Canadian studies.

Effects of Phenylcapsaicin on Intraocular and Ocular Perfusion Pressure During a 30-Min Cycling Task: A Placebo-Controlled, Triple-Blind, Balanced Crossover Study.

The main objective of this placebo-controlled, triple-blind, balanced crossover study was to assess the acute effects of phenylcapsaicin (PC) intake (2.5 mg) on intraocular pressure (IOP), ocular perfusion pressure (OPP), and heart rate (HR) during a 30-min cycling task performed at 15% of the individual maximal power. Twenty-two healthy young adults performed the cycling task 45 min after ingesting PC or placebo. IOP was measured with a rebound tonometer before exercise, during cycling (every 6 min), and after 5 and 10 min of recovery. OPP was assessed before and after exercise. HR was monitored throughout the cycling task. We found an acute increase of IOP levels related to PC consumption while cycling (mean difference = 1.91 ± 2.24 mmHg; p = .007, ηp2=.30), whereas no differences were observed for OPP levels between the PC and placebo conditions (mean difference = 1.33 ± 8.70 mmHg; p = .608). Mean HR values were higher after PC in comparison with placebo intake (mean difference = 3.11 ± 15.87 bpm, p = .019, ηp2=.24), whereas maximum HR did not differ between both experimental conditions (p = .199). These findings suggest that PC intake before exercise should be avoided when reducing IOP levels is desired (e.g., glaucoma patients or those at risk). Future studies should determine the effects of different ergogenic aids on IOP and OPP levels with other exercise configurations and in the long term.

Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1 G93A (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2+ transients and reactive oxygen species (i.e., H 2 O 2 ). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.

DAB2IP associates with hereditary angioedema: Insights into the role of VEGF signaling in HAE pathophysiology.

BACKGROUND: In the recent years, there was an important improvement in the understanding of the pathogenesis of hereditary angioedema (HAE). Notwithstanding, in a large portion of patients with unknown mutation (HAE-UNK) the genetic cause remains to be identified. OBJECTIVES: To identify new genetic targets associated with HAE, a large Argentine family with HAE-UNK spanning 3 generations was studied. METHODS: Whole exome sequencing was performed on affected family members to identify potential genetic variants associated with HAE-UNK. In silico analyses and experimental studies were applied to assess the role of the identified gene variant. RESULTS: A missense variant (p.D239N) in DAB2IP was identified. The variant occurred in the C2-domain, the region interacting with vascular endothelial growth factor receptor 2 (VEGFR2). It was found to be rare, and predicted to have a detrimental effect on the functionality of DAB2IP. Protein structure modeling predicted changes in the mutant p.D239N protein structure, impacting protein stability. The p.D239N variant affected the subcellular localization of VEGFR2. Cells transfected with the DAB2IP-239N transcript exhibited an intracellular distribution, and VEGFR2 remained associated with the cell membrane. The altered localization pattern indicated reduced colocalization of the mutant protein with VEGFR2, suggesting a diminished ability of VEGFR2 binding. CONCLUSIONS: The study identified a novel missense variant (p.D239N) in DAB2IP in a family with HAE-UNK and highlighted the role of dysregulated VEGF-mediated signaling in altered endothelial permeability. DAB2IP loss-of-function pathogenic variants lead to the impairment of the endothelial VEGF/VEGFR2 ligand system and represent a new pathophysiologic cause of HAE-UNK.

Spin Energy Contributions of the Kinetic Energy Density in the Stabilization of the Metal-Ligand Interactions.

The kinetic energy (KE) density plays an essential role in the stabilization mechanism of covalent, polar covalent, and ionic bondings; however, its role in metal-ligand bindings remains unclear. In a recent work, the energetic contributions of the spin densities α and ß were studied to explain the geometrical characteristics of a series of metal-ligand complexes. Notably, the KE density was found to modulate/stabilize the spin components of the intra-atomic nucleus-electron interactions within the metal in the complex. Here, we investigate the topographic properties of the spin components of the KE density for a family of high-spin hexa-aquo complexes ([M(H2O)6]2+) to shed light on the stabilization of the metal-ligand interaction. We compute the Lagrangian, G(r), and Hamiltonian, K(r), KE densities and analyze the evolution of its spin components in the formation of two metal-ligand coordination complexes. We study Kα/ß(r) along the metal-oxygen (M-O) internuclear axis as a function of the metal. Our results indicate that K(r) is a more distance-sensitive quantity compared to G(r) as it displays topographic features at larger M-O distances. Furthermore, K(r) allows one to identify the predominant interaction mechanism in the complexes.

Mediterranean diet as a strategy for preserving kidney function in patients with coronary heart disease with type 2 diabetes and obesity: a secondary analysis of CORDIOPREV randomized controlled trial.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is recognized an independent risk factor for chronic kidney disease (CKD). The precise contribution and differential response to treatment strategies to reduce kidney dysfunction, depending on whether obesity is present alongside T2DM or not, remain to be fully clarified. Our objective was to improve our understanding of how obesity contributes to kidney function in patients with T2DM and coronary heart disease (CHD), who are highly predisposed to CKD, to assign the most effective dietary approach to preserve kidney function. METHODS: 1002 patients with CHD and estimated glomerular filtration rate (eGFR)≥30 ml/min/1.73m2, were randomized to consume a Mediterranean diet (35% fat, 22% MUFA, < 50% carbohydrates) or a low-fat diet (28% fat, 12% MUFA, > 55% carbohydrates). Patients were classified into four groups according to the presence of T2DM and/or obesity at baseline: Non-Obesity/Non-T2DM, Obesity/Non-T2DM, Non-Obesity/T2DM and Obesity/T2DM. We evaluated kidney function using serum creatinine-based estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (uACR) before and after 5-years of dietary intervention. RESULTS: Patients with Obesity/T2DM had the lowest baseline eGFR and the highest baseline uACR compared to non-diabetics (p < 0.05). After dietary intervention, the Mediterranean diet induced a lower eGFR decline in patients with Obesity/T2DM, compared to a low-fat diet but not in the other groups (p = 0.014). The Mediterranean diet, but not the low-fat diet, also reduced uACR only in patients with Obesity/T2DM (p = 0.024). CONCLUSIONS: Obesity provided an additive effect to T2DM resulting in a more pronounced decline in kidney function compared to T2DM alone when compared to non-diabetics. In patients with concomitant presence of T2DM and obesity, with more metabolic complications, consumption of a Mediterranean diet seemed more beneficial than a low-fat diet in terms of preserving kidney function. These findings provide valuable insights for tailoring personalized lifestyle modifications in secondary prevention of cardiovascular disease. TRIAL REGISTRATION: URL, http://www.cordioprev.es/index.php/en . CLINICALTRIALS: gov number, NCT00924937.