Related Conditions Research Articles

Food-Dependent Exercise-Induced Anaphylaxis: A Challenging Life-threatening Condition

Food-dependent exercise-induced anaphylaxis (FDEIA) is an uncommon but potentially life-threatening condition characterized by allergic reactions triggered by the combination of specific food ingestion and physical exertion. Despite its rarity, FDEIA poses significant diagnostic and management challenges due to its complex pathophysiology and variable clinical presentation. Diagnosis relies on careful evaluation of clinical history, symptomatology, and laboratory tests, with inherent difficulties in distinguishing FDEIA from other related conditions. Management of FDEIA involves comprehensive strategies to minimize the risk of allergic reactions through measures such as allergen avoidance, patient education, and timely administration of epinephrine. While existing treatment approaches primarily target acute reactions, ongoing research endeavors are crucial for validating emerging diagnostic and therapeutic modalities. This review offers a comprehensive overview of FDEIA, encompassing its epidemiology, underlying pathophysiology, clinical presentations, diagnostic challenges, and management approaches.

Impact of Lactocaseibacillus (Lactobacillus) paracasei sup. paracasei TISTR 2593 Probiotic Supplementation on the Gut Microbiome of Hypercholesterolemia Patients: A Randomized Controlled Trial.

Probiotics have shown potential in managing hypercholesterolemia and related metabolic conditions. This study evaluated the effects of Lactocaseibacillus (Lactobacillus) paracasei sup. paracasei TISTR 2593 on the gut microbiome and metabolic health in patients with hypercholesterolemia, and was registered in the Thai Clinical Trial Registry (TCTR 20220917002). In a randomized, double-blind, placebo-controlled trial, 22 hypercholesterolemic participants received either the probiotic or a placebo daily for 90 days. Fecal samples collected before and after the intervention revealed significant microbiome changes, including a decrease in Subdoligranulum, linked to rheumatoid arthritis, and an increase in Flavonifractor, known for its anti-inflammatory properties. Additionally, the probiotic group exhibited a significant reduction in low-density lipoprotein cholesterol (LDL-C) levels. These findings suggest that L. paracasei TISTR 2593 can modulate the gut microbiome and improve metabolic health, warranting further investigation into its mechanisms and long-term benefits.

Floodplains as a Suitable Habitat for Freshwater Fish: The Length–Weight Relationships and Condition Factors of Fish Inhabiting a Danube Floodplain in Croatia

When studying the well-being and fitness of ichthyofauna in a specific area, vital information comes from length–weight relationships (LWRs) and condition factor analyses and calculations. Data were collected from 2015 to 2019 in an area important for fish shelter, feeding, and spawning. Twenty four species belonging to 10 different families were identified from the total 16,895 of caught individuals, with the most abundant species being Blicca bjoerkna. The calculation of LWRs was possible for 19 species, (R2 = 0.7049–0.9998 (p < 0.05)), with the values of the mean coefficient b ranging from 2.6831 to 3.5747, indicating an overall positive allometric growth in the fish population. The results of Fulton’s and the relative condition factors showed that a total of eight species were in a relatively good condition, although the species in question varied between the two condition factors. Fulton’s condition factor showed the highest average value for Lepomis gibbosus (1.4956), while Cobitis elongatoides had the lowest (0.4739). Contrarily, the relative condition factor showed the highest average value for Silurus glanis (1.0524), and the lowest for Gymnocephalus cernua (1.0023). The lower values of calculated condition factors in some species could be attributed to sampling being conducted during the colder months of autumn and winter. Future studies should include seasonal sampling in order to achieve a better understanding how various abiotic factors impact the condition factors of these fish species. Nevertheless, this research provided valuable data on the status of the fish population in the floodplain and could be used as a guideline for designing future ichthyofauna studies in this area.

Assessment of Nutraceuticals Potentials of Protein Isolates from Seed Coat of Four Melon Species

Recently, there has been more attention on the bioactivity of phytochemicals and other metabolites in agro-food by-products for the management of oxidative stress–related conditions. Hence, the objective of this paper is to assess the nutraceuticals potential by investigating antioxidant and α-amylase inhibitory potentials of seed coat protein isolates from four melon species namely: Citrullus colocynthis, Citrullus mucosospermus, Cucumeropsis mannii and Lagenaria siceraria using appropriate standard methods. At highest concentration, Lagenaria siceraria had the strongest free radical scavenging activity (38% inhibition). The strongest chelating effect was exhibited by C. mannii (IC50 = 0.59 ± 0.08 mg/ml), which also showed highest ferric reducing potential at all concentrations. At 0.05 mg/ml, C. colocynthis, C. mucosospermus, C. mannii, and L. siceraria seed coat protein extracts inhibited alpha-amylase activity by 43.2%, 16.76%, 2.6% and 22.3%, respectively, and inhibition of 60.9%, 28.6%, 38.3% and 29.5% were recorded for the seed protein extracts respectively, at 0.5 mg/ml. In conclusion, the various melon seed coat protein isolates showed appreciable levels of antioxidants and possessed inhibitory activity against α-amylase. Hence, the seed coats of the four melon varieties assessed in this study are promising potential sources of antioxidants for the supplementary treatment of oxidative stress–induced conditions.

Defining a Nation: Métis Nation Building in the Face of Epistemic Injustice

Abstract: Over the past four decades, Indigenous political claims "in" Canada have come increasingly to assume a nationalist form. Efforts at instilling a national identity play an abundantly clear role in Indigenous nation (re)building: they hold the potential to concretize internal solidarity, mobilize community to pursue long-term goals, and they aid in overcoming a host of collective action problems. However, for national claims to play such a role, it is necessary that outside groups recognize a community's national identity and accept it as distinct. That is to say, nationhood must be thought about in terms of its occurrence in an (unequally) relational context: claims to a national distinction occur in competition with other claims, in a field of struggle and competition in which actors possess varying abilities to enforce/support claims and to have those claims recognized by others. In this regard, the concept of epistemic injustice is especially useful to engage with the differential capacity of communities to claim and enforce national claims unto others. Our analysis, which focuses specifically on the case of the Métis, pays particular attention to the widespread misrecognitions that occur when a dominant social group marginalizes Métis claims to nationhood. Through this exploration, our article contributes to a better understanding of relational conditions overall and the ways in which identity and nationhood can support the process of Indigenous nation building.

Stock assessment of rosy barb, Pethia conchonius (Hamilton, 1822) in Dal Lake of Kashmir Himalayas

For management of fish stocks, assessing the various parameters of population dynamics are regarded as being extremely important. Under this backdrop the population dynamics parameters viz. growth, mortality and recruitment of Pethia conchonius, inhabiting the Dal Lake of Kashmir Himalayas were analysed using FiSAT II software. The analysed specimens were collected from five different sites within the lake and exhibited a total weight range of 0.3 to 6.4 g and a total length range of 3.1 to 7.8 cm. The relative condition factor for the fish was reported to be 1.11. The growth parameter i.e., asymptotic length, age at zero length, growth performance index and growth constant were reported to be 10.0 cm, –0.75 years, 1.48 and 0.30 year–1 respectively. The total mortality of 1.49 year–1, consisting of natural mortality of 0.88 year–1 and fishing mortality of 0.61 year–1 was reported. An exploitation rate of 0.41 is suggestive of a less exploited state of the fish. The length at first maturity was found to be higher than the length at first capture, a condition that can disturb the stock, as such the utility of a net with relatively larger mesh size is advisable. The current research on the population dynamics of P. conchonius can be used as the baseline data for its management practices.

Modulation of liver cholesterol homeostasis by choline supplementation during fibrosis resolution

Liver fibrosis is a critical global health challenge, often leading to severe liver diseases without timely intervention. Choline deficiency has been linked to metabolic dysfunction associated steatohepatitis (MASH) and liver fibrosis, suggesting choline supplementation as a potential therapeutic approach. This study aimed to explore the therapeutic potential of choline supplementation in liver fibrosis resolution and its effects on cholesterol homeostasis using a mouse model with induced liver fibrosis. Our findings reveal that choline supplementation significantly decreases blood lactate dehydrogenase (LDH) and non-high-density lipoprotein cholesterol (non-HDL-C) levels. Transcriptome analysis showed that choline supplementation primarily induces genes related to cholesterol homeostasis, suggesting a significant impact on liver cholesterol synthesis. However, choline supplementation did not significantly alter the expression of fibrosis-related, choline metabolism-related, or epigenetics-related genes. This study provides novel insights into the role of choline in liver health and cholesterol metabolism, potentially informing treatments for liver fibrosis and related conditions.

Enhanced acetone gas sensor via TiO2 nanofiber-NiO nanoparticle heterojunction

We present a high surface area sensor comprising NiO nanoparticles (NPs) incorporated within porous TiO2 nanofibers (NFs), showing a remarkable response to acetone. Initially, we synthesized Polyvinylpyrrolidone (PVP) NFs containing titanium (Ti) and nickel (Ni) salts using a simple electrospinning method. Subsequent calcination of the PVP NFs led to the formation of NiO NPs embedded within the porous TiO2 NFs. The resulting heterostructure material exhibited a significant response to acetone detection, with a ratio of electrical resistance in air (Ra) to that in the presence of gas (Rg) reaching 83 at its optimal operating temperature of 300 °C. Furthermore, it demonstrated stable performance under high relative humidity conditions.

Genetic and Environmental Factors Co-Contributing to Behavioral Abnormalities in adnp/adnp2 Mutant Zebrafish.

Human mutations of ADNP and ADNP2 are known to be associated with neural developmental disorders (NDDs), including autism spectrum disorders (ASDs) and schizophrenia (SZ). However, the underlying mechanisms remain elusive. In this study, using CRISPR/Cas9 gene editing technology, we generated adnp and adnp2 mutant zebrafish models, which exhibited developmental delays, brain deficits, and core behavioral features of NDDs. RNA sequencing analysis of adnpa-/-; adnpb-/- and adnp2a-/-; adnp2b-/- larval brains revealed altered gene expression profiles affecting synaptic transmission, autophagy, apoptosis, microtubule dynamics, hormone signaling, and circadian rhythm regulation. Validation using whole-mount in situ hybridization (WISH) and real-time quantitative PCR (qRT-PCR) corroborated these findings, supporting the RNA-seq results. Additionally, loss of adnp and adnp2 resulted in significant downregulation of pan-neuronal HuC and neuronal fiber network α-Tubulin signals. Importantly, prolonged low-dose exposure to environmental endocrine disruptors (EEDs) aggravated behavioral abnormalities in adnp and adnp2 mutants. This comprehensive approach enhances our understanding of the complex interplay between genetic mutations and environmental factors in NDDs. Our findings provide novel insights and experimental foundations into the roles of adnp and adnp2 in neurodevelopment and behavioral regulation, offering a framework for future preclinical drug screening aimed at elucidating the pathogenesis of NDDs and related conditions.

A conditional multi-label model to improve prediction of a rare outcome: An illustration predicting autism diagnosis

ObjectiveThis study aimed to develop a novel approach using routinely collected electronic health records (EHRs) data to improve the prediction of a rare event. We illustrated this using an example of improving early prediction of an autism diagnosis, given its low prevalence, by leveraging correlations between autism and other neurodevelopmental conditions (NDCs). MethodsTo achieve this, we introduced a conditional multi-label model by merging conditional learning and multi-label methodologies. The conditional learning approach breaks a hard task into more manageable pieces in each stage, and the multi-label approach utilizes information from related neurodevelopmental conditions to learn predictive latent features. The study involved forecasting autism diagnosis by age 5.5 years, utilizing data from the first 18 months of life, and the analysis of feature importance correlations to explore the alignment within the feature space across different conditions. ResultsUpon analysis of health records from 18,156 children, we are able to generate a model that predicts a future autism diagnosis with moderate performance (AUROC=0.76). The proposed conditional multi-label method significantly improves predictive performance with an AUROC of 0.80 (p < 0.001). Further examination shows that both the conditional and multi-label approach alone provided marginal lift to the model performance compared to a one-stage one-label approach. We also demonstrated the generalizability and applicability of this method using simulated data with high correlation between feature vectors for different labels. ConclusionOur findings underscore the effectiveness of the developed conditional multi-label model for early prediction of an autism diagnosis. The study introduces a versatile strategy applicable to prediction tasks involving limited target populations but sharing underlying features or etiology among related groups.

Take-home naloxone administered in emergency settings: feasibility of intervention implementation in a cluster randomized trial

BackgroundOpioids kill more people than any other class of drug. Naloxone is an opioid antagonist which can be distributed in kits for peer administration. We assessed the feasibility of implementing a Take-home Naloxone (THN) intervention in emergency settings, as part of designing a definitive randomised controlled trial (RCT).MethodsWe undertook a clustered RCT on sites pairing UK Emergency Departments (ED) and ambulance services. At intervention sites, we recruited emergency healthcare practitioners to supply THN to patients presenting with opioid overdose or related condition, with recruitment across 2019–2021. We assessed feasibility of intervention implementation against four predetermined progression criteria covering site sign up and staff training; identification of eligible patients; issue of THN kits and Serious Adverse Events.ResultsAt two intervention sites, randomly selected from 4, 299/687 (43.5%) clinical staff were trained (ED1 = 107, AS1 = 121, ED2 = 25, AS2 = 46). Sixty THN kits were supplied to eligible patients (21.7%) (n: ED1 = 36, AS1 = 4, ED2 = 16, AS2 = 4). Across sites, kits were not issued to eligible patients on a further 164 occasions, with reasons reported including: staff forgot (n = 136), staff too busy (n = 15), and suspected intentional overdose (n = 3), no kit available (n = 2), already given by drugs nurse (n = 4), other (n = 4). Staff recorded 626 other patients as ineligible but considered for inclusion, with reasons listed as: patient admitted to hospital (n = 194), patient absconded (n = 161) already recruited (n = 64), uncooperative or abusive (n = 55), staff not trained (n = 43), reduced consciousness level (n = 41), lack of capacity (n = 35), patient in custody (n = 21), other (n = 12). No adverse events were reported.ConclusionStaff and patient recruitment were low and varied widely by site. This feasibility study did not meet progression criteria; a fully powered RCT is not planned.Trial RegistrationISRCTN13232859 (Registered 16/02/2018).

Chemical composition, anti-hypertensive properties, and sensory attributes of salt extracted from ash of Hygrophilia schulli.

The traditional usage of salt taken from vegetables for the treatment of blood pressure and diabetes is seen in several regions of Ethiopia, particularly in Gambella. The aim of the study was to investigate the mineral content, anti-hypertensive properties, and sensory attributes of salt obtained from the Hygrophilia schulli. The salt was extracted from the ashing of stems of Hygrophilia schulli. Optical Emission Spectroscopy with Inductively Coupled Plasma was used to identify macro-minerals, micro-minerals, and some toxic metals. Flame Atomic Absorption Spectroscopy was used to assess the levels of arsenic and mercury. The anti-hypertensive property of the salt was determined invivo using the Wistar rats. The extracted salt was rich in potassium and was deficient in sodium from the analyzed macro-minerals. It was free from mercury, cadmium, chromium, and arsenic. Lead and nickel were below the Tolerable Weekly Intake Provisional specified by the European Union. Among carbonate and sulfate, chloride was the main anion in this salt. The salt was discovered to have a low taste characteristic compared to common salt. However, the taste attribute of the combination of vegetable and common salt in different proportions was better than common salt. Rats fed with salt from Hygrophilia schulli showed a statistically significant lower systolic, diastolic, and mean blood pressure compared to normal-fed and common salt-fed rat groups. Generally, this study suggests that Hygrophilia schulli salt has the potential to be a viable alternative to common salt, particularly for those suffering from hypertension and other related chronic conditions.

Numerical study of gas crossover effect on hydrogen-oxygen proton exchange membrane fuel cell

Hydrogen-oxygen proton exchange membrane fuel cell (H2/O2 PEMFC) is a typical fuel cell for the applications of air-free environments, such as aerospace and underwater. Gas crossover has an adverse effect on the cell performance especially on open-circuit voltage (OCV), and this phenomenon would be severe for H2/O2 PEMFC. In this study, we develop a H2/O2 PEMFC model considering hydrogen and oxygen crossover, and investigate the gas crossover effect on H2/O2 PEMFC, and effects of temperature, relative humidity, inlet pressure and membrane thickness. The numerical results show that the gas crossover effect on the cell performance is obvious in the low current density region, and this effect becomes weak with current density. Although the crossover flux rate of hydrogen is generally greater than that of oxygen, the crossover current density of oxygen could be greater than that of hydrogen. Increasing temperature and relative humidity will decrease the OCV, and increase hydrogen and oxygen crossover current density. The temperature effect on OCV is more obvious at high relative humidity conditions. Increasing inlet pressure only slightly increases the OCV with considering the gas crossover effect. The OCV increases with increasing membrane thickness, and this positive effect becomes weak when the membrane thickness is greater than 75 μm in the investigated range. The work illustrates the basic influence rules and some quantified results of the critical parameters on the gas crossover effect and OCV of H2/O2 PEMFC.

Glutamic-Alanine Rich Glycoprotein from Undaria pinnatifida: A Promising Natural Anti-Inflammatory Agent.

This study aimed to assess the anti-inflammatory properties of a bioactive glutamic-alanine rich glycoprotein (GP) derived from Undaria pinnatifida on both LPS-stimulated RAW264.7 cells, peritoneal macrophages, and mouse models of carrageenan- and xylene-induced inflammation, investigating the underlying molecular mechanisms. In both in-vitro and in-vivo settings, GP was found to reduce the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) while also inhibiting the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in response to lipopolysaccharide (LPS) stimulation. GP treatment significantly impeded the nuclear translocation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway by blocking the phosphorylation of IKKα and IκBα, leading to a reduction in proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Additionally, GP effectively inhibited the activation of mitogen-activated protein kinases (MAPKs), with specific inhibitors of p38 and extra-cellular signal regulated kinase (ERK) enhancing GP's anti-inflammatory efficacy. Notably, GP administration at 10 mg/kg/day (p.o.) markedly reduced carrageenan-induced paw inflammation and xylene-induced ear edema by preventing the infiltration of inflammatory cells into targeted tissues. GP treatment also downregulated key inflammatory markers, including iNOS, COX-2, IκBα, and NF-κB, by suppressing the phosphorylation of p38 and ERK, thereby improving the inflammatory index in both carrageenan- and xylene-induced mouse models. These findings suggest that marine resources, particularly seaweeds like U. pinnatifida, could serve as valuable sources of natural anti-inflammatory proteins for the effective treatment of inflammation and related conditions.

Towards spatially selective efferent neuromodulation: anatomical and functional organization of cardiac fibres in the porcine cervical vagus nerve.

Spatially selective vagus nerve stimulation (sVNS) offers a promising approach for addressing heart disease with enhanced precision. Despite its therapeutic potential, VNS is limited by off-target effects and the need for time-consuming titration. Our research aimed to determine the spatial organization of cardiac afferent and efferent fibres within the vagus nerve of pigs to achieve targeted neuromodulation. Using trial-and-error sVNS in vivo and ex vivo micro-computed tomography fascicle tracing, we found significant spatial separation between cardiac afferent and cardiac efferent fibres at the mid-cervical level and they were localized on average on opposite sides of the nerve cross-section. This was consistent between both in vivo and ex vivo methods. Specifically, cardiac afferent fibres were located near pulmonary fibres, consistent with findings of cardiopulmonary convergent circuits and, notably, cardiac efferent fascicles were exclusive. These cardiac efferent regions were located in close proximity to the recurrent laryngeal regions. This is consistent with the roughly equitable spread across the nerve of the afferent and efferent fibres. Our study demonstrated that targeted neuromodulation via sVNS could achieve scalable heart rate decreases without eliciting cardiac afferent-related reflexes; this is desirable for reducing sympathetic overactivation associated with heart disease. These findings indicate that understanding the spatial organization of cardiac-related fibres within the vagus nerve can lead to more precise and effective VNS therapy, minimizing off-target effects and potentially mitigating the need for titration. KEY POINTS: Spatially selective vagus nerve stimulation (sVNS) presents a promising approach for addressing chronic heart disease with enhanced precision. Our study reveals significant spatial separation between cardiac afferent and efferent fibres in the vagus nerve, particularly at the mid-cervical level. Utilizing trial-and-error sVNS in vivo and micro-computed tomography fascicle tracing, we demonstrate the potential for targeted neuromodulation, achieving therapeutic effects such as scalable heart rate decrease without stimulating cardiac afferent-related reflexes. This spatial understanding opens avenues for more effective VNS therapy, minimizing off-target effects and potentially eliminating the need for titration, thereby expediting therapeutic outcomes in myocardial infarction and related conditions.

Distinct biophysiological effects of Ramadan fasting and traditional intermittent fasting on markers of body fat storage. A real-life study

BackgroundRamadan Intermittent fasting (RIF) exerts beneficial metabolic effects and improves gastrointestinal motility. However, a comparison between RIF and the traditional 16-hours intermittent fasting (16IF), a strategy for weight loss, is lacking. MethodsA total of 34 subjects (median age 32.5 years, range 18–63 years; median BMI 24.5 Kg m-1², range 18.6–37.6 Kg m-1²) were assigned to RIF (N = 18) or 16IF (N = 16) for 30 days. We measured variations in anthropometric measures (BMI, waist, and abdominal circumference), serum insulin, glucose, cortisol, non-esterified fatty acid (NEFA), body fat composition (bioelectrical impedance analysis), and the ultrasonographic measurements of liver steatosis (Hepatorenal index, HRI) and thickness of subcutaneous (SAT) and visceral (VAT) fats. ResultsAt baseline, BMI, rates of liver steatosis and distribution of normal weight, overweight, and obese subjects were comparable between the two groups. Body weight significantly decreased at the end of fasting in both RIF (-4.2 % vs baseline, P = 0.002) and 16IF (-2.1 % vs baseline, P = 0.002). Waist and abdominal circumferences significantly decreased only in RIF as well as the amount of body fat. In subjects with liver steatosis, SAT and VAT significantly decreased following RIF, but not 16h-IF, as well as the ultrasonographic HRI. ConclusionBoth 16IF and RIF are able, during 1-month, to reduce body weight. However, RIF but not 16IF also generates marked beneficial effects in terms of reduced subcutaneous fat and liver steatosis. Further studies urge to verify the effects of different models of IF in weight-cycling and long-term management of obesity and related dysmetabolic conditions, such as ectopic fat over-storage.

Thermo-hydro-mechanical viscoplastic constitutive model for polyester strap reinforcement long-term response

Polymeric materials have been shown to be rate-dependent materials, that is, their response will vary depending on the conditions to which they are subjected. The present work details the formulation, validation and implementation of a viscoplastic constitutive model with stress, strain, temperature, and relative humidity dependencies aimed to simulate the long-term response of polymeric materials, particularly that of polyester. The model is capable of predicting primary and secondary creep, often observed in geosynthetic materials. Both creep mechanisms can be modelled independently if needed. For calibration, a wide data-set of polyester strap reinforcement creep measurements was used. The validation process was done using parameters for load-, product-, and material-specific scenarios. Load- and product-specific scenarios showed suitable agreement between simulated and measured data. The coupled capabilities of the model are shown via variable temperature and relative humidity boundary conditions. Due to lack of data, temperature and relative humidity dependencies represent idealized scenarios. Simulations of stress-relaxation response for constant rate of strain scenarios are also provided. The proposed formulation is aimed at modelling the mechanical response of reinforced soil structures while accounting for the effect of in-air or in-soil conditions to which reinforcement materials can be exposed to throughout the structure’s life-cycle.

Longitudinal characterization of impulsivity phenotypes boosts signal for genomic correlates and heritability.

Genomic correlates of impulsivity have been identified in several genome-wide association studies (GWAS) using cross-sectional designs, but no studies have investigated the molecular genetic correlates of impulsivity phenotypes using longitudinally constructed traits. In 3860 unrelated European participants in the Avon Longitudinal Study of Parents and Children (ALSPAC), we constructed longitudinal phenotypes for delay discounting and impulsive personality traits (as measured by the UPPS-P impulsive behavior scales) via assessment at ages 24, 26, and 28. We conducted GWASs of impulsivity using both cross-sectional and longitudinal phenotypes, estimated heritability and their phenotypic and genetic correlations, and evaluated their association with recently-developed polygenic risk scores (PRSs) for the impulsivity indicators themselves and also related psychiatric conditions. Latent growth curve modeling revealed a stable intercept over time for all impulsivity phenotypes. High genetic correlation of cross-sectional measures over time suggested a stable genetic component for delay discounting (rg = 0.53-0.99) and sensation seeking (rg = 0.99). Heritability estimates of the stable longitudinal phenotypes substantively improved as compared to their cross-sectional counterparts, revealing a significant SNP-heritability for delay discounting (0.22; p = 0.03) and sensation seeking (0.35; p = 0.0007). Consistent with previous reports, GWAS and gene-based analyses revealed associations between specific longitudinal impulsivity indicators and CADM2 and NCAM1 genes. The PRSs for the impulsivity indicators and disorders related to self-regulation were also significantly associated with longitudinal impulsivity traits. Finally, we validated the associations between longitudinal impulsivity phenotypes and their PRSs in an independent 13-wave longitudinal study (n = 1019) and the benefit of longitudinal phenotypes in simulation studies. In this first longitudinal genetic study of impulsivity traits, the results revealed stable genomic correlates of delay discounting and sensation seeking over time and further validated the utility of recently-developed PRSs, both in relation to the observed traits and in connecting them to psychiatric disorders. More generally, these findings support using latent intercepts as novel longitudinal phenotypes to boost signal for heritability and genomic correlates of mechanisms contributing to psychiatric disease liability.

Mesenchymal stem cells from adipose tissue prone to lose their stemness associated markers in obesity related stress conditions

Obesity is a health problem characterized by large expansion of adipose tissue. During this expansion, genotoxic stressors can be accumulated and negatively affect the mesenchymal stem cells (MSCs) of adipose tissue. Due to the oxidative stress generated by these genotoxic stressors, senescence phenotype might be observed in adipose tissue MSCs. Senescent MSCs lose their proliferations and differentiation properties and secrete senescence-associated molecules to their niche thus triggering senescence for the rest of the tissue. Accumulation of senescent cells in adipose tissue results in decreased tissue regeneration and functional impairment not only in the close vicinity but also in the other tissues. Here we hypothesized that declined tissue regeneration might be associated with loss of stemness markers in MSCs population. We analyzed the expression of several stemness-associated genes of in vitro cultured MSCs originated from adipose tissue of high-fat diet and normal diet mice models. Since the heterogenous MSCs population covers a small percentage of the pluripotent stem cells, which have roles in proliferation and tissue regeneration, we measured the percentage of these cells via TRA-1-60 pluripotent state antigen. Additionally, by conducting a shotgun proteomic approach using LC-MS/MS, whole cell proteome of the adipose tissue MSCs of high-fat diet and normal diet mice were analyzed and identified proteins were evaluated via gene ontology and PPI network analysis. MSCs of obese mice showed senescent phenotype and altered cell cycle distribution due to a hostile environment with oxidative stress in adipose tissue where they reside. Additionally, the number of pluripotent markers expressing cells declined in the MSC population of the high-fat diet mice. Gene expression analysis evidenced the loss of stemness with a decrease in the expression of stemness-associated genes. Of the proteomic comparison of the normal and the high-fat diet group, MSCs revealed that stemness-associated molecules were decreased while inflammation and senescence-associated phenotypes emerged in obese mice MSCs. Our results showed us that the MSCs of adipose tissue may lose their stemness properties due to obesity-associated stress conditions.

A first-in-kind MAPK13 inhibitor that can correct stem cell reprogramming and post-injury disease.

The stress kinase MAPK13 (aka p38δ-MAPK) is an attractive entry point for therapeutic intervention because it regulates the structural remodeling that can develop after epithelial barrier injury in the lung and likely other tissue sites. However, a selective, safe, and effective MAPK13 inhibitor is not yet available for experimental or clinical application. Here we identify a first-in-kind MAPK13 inhibitor using structure-based drug design combined with a screening funnel for cell safety and molecular specificity. This inhibitor (designated NuP-4) down-regulates basal-epithelial stem cell reprogramming, structural remodeling, and pathophysiology equivalently to Mapk13 gene-knockout in mouse and mouse organoid models of post-viral lung disease. This therapeutic benefit persists after stopping treatment as a sign of disease modification and attenuates key aspects of inflammation and remodeling as an indication of disease reversal. Similarly, NuP-4 treatment can directly control cytokine-stimulated growth, immune activation, and mucinous differentiation in human basal-cell organoids. The data thereby provide a new tool and potential fix for long-term stem cell reprogramming after viral injury and related conditions that require MAPK13 induction-activation.