Developing lightweight and effective radiation shields is a critical challenge for many applications, from medical facilities to space missions. In this study, we present a novel polyurethane (PU) foam composite reinforced with a mixture of B4C, PbO, and CdO fillers to enhance both gamma and neutron radiation shielding. Using a combination of Monte Carlo simulations (MCNP6 and GEANT4) and experimental measurements, we systematically evaluated the gamma attenuation properties of these composites with varying filler concentrations. Our results show that increasing filler content significantly improves the shielding performance, achieving a lead-equivalent thickness of up to 0.21 cm at a gamma energy of 0.662 MeV, while maintaining the lightweight and flexible nature of the polymer. Neutron shielding simulations reveal that B4C and CdO effectively absorb neutrons, contributing to a multifunctional shield design. Microstructural analyses by FESEM and XRD confirm uniform filler dispersion and preserved crystalline structure within the polymer matrix, which are key factors for reliable shielding performance. This work highlights the potential of PU-based composites as versatile, practical alternatives to traditional heavy and bulky radiation shields, opening avenues for safer and more adaptable protection solutions.
Temporal lobe epilepsy (TLE), particularly mesial temporal lobe epilepsy (MTLE), often presents with visual working memory (VWM) impairments, with potential heterogeneity between hippocampal sclerosis (HS) and MRI-negative subtypes. However, task-related electrophysiological (EEG) evidence regarding brain network alterations during VWM processing in MTLE remains limited. This study aims to identify shared brain network alterations and their behavioral correlates in patients with MTLE and to further characterize subtype-specific differences between HS-MTLE and MRI negative-MTLE. We recruited 60 right-handed participants, including 30 patients with MTLE (12 HS-MTLE, 18 MRI negative-MTLE) and 30 healthy controls (HCs). All participants completed the Chinese version of the Wechsler Memory Scale-Revised (WMS-RC) and performed a VWM task during simultaneous EEG recording. Graph theory analysis was used to assess the in-degree and out-degree of directed functional networks in the theta and gamma frequency bands; the results were correlated with clinical and cognitive behavioral indicators. Behaviorally, patients with MTLE showed significant VWM impairments compared with HCs, with no significant difference between HS and MRI-negative subtypes. Common network alterations in patients with MTLE included decreased theta-band connectivity from occipital to temporal regions, with this theta-band connectivity significantly associated with slower task responses and reduced accuracy. In subgroup analysis, the HS-MTLE group showed reduced theta outflow and abnormally enhanced gamma activity in posterior occipital regions. Conversely, the MRI negative-MTLE group showed more widespread increases in gamma-band in-degree and out-degree across anterior regions, including prefrontal, frontocentral, and temporal areas. Patients with MTLE share a common alteration in occipital-to-temporal information transfer during VWM. Exploratory analyses suggest distinct network alterations between HS-MTLE and MRI negative-MTLE, presenting with abnormalities in posterior and anterior networks, respectively. These hypothesis-generating findings provide electrophysiological evidence to support precise subtyping of MTLE and targeted cognitive intervention development.
Transcranial alternating current stimulation (tACS) with a combined theta-gamma (TG) waveform can boost human motor performance, but its effects on primary motor cortex (M1) plasticity remain unclear. This study investigated the effects of concurrent TG tACS and repetitive paired-pulse transcranial magnetic stimulation (rppTMS) on M1 excitability and plasticity. A total of 22 healthy young adults completed four experimental sessions involving concurrent application of tACS and rppTMS over M1. Fifteen minutes of rppTMS (1.5 ms interstimulus interval, [ISI]) was applied during tACS with either a 75-Hz gamma burst nested in the peak (TGP) or trough (TGT) of a 6-Hz theta carrier wave, theta in isolation (TP), or sham (ten second ramp at start/end). Single- and paired-pulse TMS was performed before and after the rppTMS intervention to assess motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (2 ms ISI), and short-interval intracortical facilitation (1.5 ms ISI). Paired-pulse MEP amplitude during rppTMS (online effects) increased with active (TGP, TGT, TP; all p < 0.045) but not sham (all p > 0.222) tACS. In contrast, examination of offline responses showed that single-pulse MEP amplitude and short-interval intracortical facilitation increased, whereas short-interval intracortical inhibition decreased, after the intervention (all p < 0.008), but this change was not different across tACS conditions (all p > 0.050). Our study shows that tACS resulted in an increase in M1 excitability during rppTMS, but this was not different between peak- and trough-coupled TG tACS, or theta tACS. Furthermore, TG tACS did not influence offline neuroplastic effects with rppTMS. As these studies were performed at rest, it is possible that tACS may be more effective during a motor task that activates a broader motor network.
T-cell responses are important for controlling viral infections, but underutilized in routine diagnostics. In recent years, whole-blood interferon-gamma release assays (IGRAs) have emerged as a simple and reliable method for detecting virus-specific T-cells, making them well suited for clinical use. Monitoring of Epstein-Barr virus (EBV) infection is clinically important in transplant recipients and EBV-associated conditions such as Multiple Sclerosis (MS). However, serological assessment may be confounded by disease-modifying treatments, making T-cell-based assays a robust approach for determining EBV-specific immune status. To develop a whole-blood IGRA for the detection of EBV-specific T-cells and to apply it in a clinical context i.e. in patients with MS (pwMS). Blood samples from 50 healthy individuals (HI) and 20 pwMS were stimulated with EBNA1 and one self-designed pool (EIHM). IFNγ levels were measured via ELISA and compared to anti-VCA IgG serostatus. The IGRA reliably detected EBV-specific T-cell responses in HI with prior EBV infection using the EBNA1 and EIHM pools. Anti-VCA IgG-positive HI showed significantly higher IFNγ level than EBV-seronegative HI (p < 0.0001), and these responses correlated with anti-VCA IgG levels (EBNA1: p < 0.0001, rs = 0.54; EIHM: p < 0.0001, rs = 0.72). In pwMS, EBV-specific T-cell responses were detectable before therapy and tended to be higher than in HI. After anti-CD20 treatment, EBV-specific IFNγ responses declined significantly (EBNA1: p = 0.0020; EIHM: p = 0.0078). The EBV IGRA reliably detects EBV-specific T-cells in seropositive individuals and enables monitoring of cellular immunity in clinical settings.
Reliable theoretical reaction cross sections require nuclear structure inputs that remain physically meaningful over different projectile types, mass regions and reaction mechanisms. In this work, the influence of collective nuclear motion on calculated cross sections was re-examined for four benchmark like reactions: 47Ti(d,2p)47Sc, 74Ge(γ,2n)72Ge, 111Cd(p,n)111In and 160Gd(n,γ)161Gd. Cross section curves obtained with the Collective Semi-Classical Fermi Gas Model (CSCFGM) were compared with EXFOR measurements, default TALYS calculations and TENDL-2025 evaluated residual production data. The analysis shows that the CSCFGM description reproduces the principal experimental features, including threshold behavior, peak location and post peak decrease or saturation, while the degree of improvement depends on the dominant reaction mechanism. The strongest peak agreement is obtained for the 74Ge(γ,2n)72Ge and 111Cd(p,n)111In reactions. The 47Ti(d,2p)47Sc and 160Gd(n,γ)161Gd cases indicate additional sensitivity to deuteron breakup, optical model parameters, gamma ray strength functions and resonance like neutron capture behavior. A dedicated gamma strength sensitivity test for 74Ge(γ,2n)72Ge further demonstrates that the photonuclear peak magnitude cannot be interpreted from the NLD input alone. The novelty of the study is the reaction by reaction evaluation of a common collective NLD framework against experimental data, default TALYS and TENDL, thereby identifying both the predictive value and the limitations of collective enhancement in model based nuclear data calculations.
Low-light images often suffer from reduced visibility, noise, and loss of structural details due to insufficient illumination and sensor limitations. These degradations affect both visual perception and downstream image analysis tasks. This paper presents a low-light image enhancement framework based on intuitionistic fuzzy generator (IFG) integrated with gamma correction and optimized using particle swarm optimization (PSO). As a preprocessing step, block-matching and 3D filtering (BM3D) are applied to suppress noise while preserving structural information. The IFG models uncertainty in pixel intensities to enable adaptive contrast enhancement, whereas gamma correction adjusts brightness levels. The enhancement parameters are optimized using PSO guided by dataset-specific objective functions, namely structural similarity (SSIM) for reference datasets and entropy-based optimization for no-reference scenarios where ground-truth images are unavailable. Experimental evaluations on standard benchmark datasets using both reference and no-reference image quality metrics indicate that the proposed framework achieves competitive enhancement performance with improved contrast and preservation of visually relevant image details. Although the computational cost is higher than that of feed-forward deep learning models, the framework is suitable for applications where training data are unavailable and interpretable parameter-adaptive enhancement is preferred.
Monoclonal gammopathies represent a spectrum of clinical and biological abnormalities characterized by monoclonal immunoglobulin production from plasma cell clones. In kidney transplant recipients, monoclonal gammopathies and their identification constitute a complex and multifactorial phenomenon involving immunological alterations and underlying pathologies such as multiple myeloma or lymphoproliferative diseases. We retrospectively studied patients who underwent kidney transplant at the Nephrology Department of Sahloul University Hospital from November 1, 2007, to December 31, 2024, and who had detection of monoclonal gammopathies during follow -up. Among 332 kidney transplant recipients, 10 (3.0 % ) developed monoclonal gammopathies. Mean age was 42.4 years (range, 27 -58 years ), with male predominance (70 % ). Hypertension was the most frequent comorbidity (50 % ). Only 1 patient had preexisting monoclonal gammopathies before transplant. Chronic interstitial nephropathy was the most common initial nephropathy (62.5 % ). Mean time to diagnosis of monoclonal gammopathies posttransplant was 58.9 months. Serum protein electrophoresis revealed monoclonal peaks in the gamma -globulin region (70 % ), beta -1 globulin (20 % ), and beta -2 globulin (10 % ). Immunofixation showed immunoglobulin G lambda (40 % ), immunoglobulin G kappa, immunoglobulin A lambda and kappa, and isolated light chains. Proteinuria was present in 60 % and anemia in 70 % of cases. Evolution included return to hemodialysis in 3 patients, infectious complications in 4 patients, and 1 death. The effect of monoclonal gammopathies on kidney transplant recipients remains an evolving research domain where diagnostic and therapeutic advances play a key role in improving management of these vulnerable patients.
The present study examined the impact of conjugated linoleic acid (CLA) on the differentiation and proliferation of bovine intramuscular preadipocyte (BIP) cells, specifically exploring the role of G protein-coupled receptor 41 (GPCR41). Cells were exposed to CLA at various concentrations ranging from 50 to 150 μmol/L. Flow cytometry revealed that treatment with 100 μmol/L CLA led to a significant increase in the proliferation rate. During differentiation, 100 and 150 μmol/L CLA markedly enhanced lipid droplet accumulation. Maximal cytoplasmic lipid content was observed when CLA was combined with insulin and dexamethasone. CLA treatment significantly enhanced the transcript abundance of the adipogenic transcription factors peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT-enhancer binding protein alpha (C/EBPα). Knockdown of GPCR41 via RNA interference in CLA-treated cells led to a significant suppression of GPCR41 expression, accompanied by decreased PPARγ mRNA levels and diminished cytoplasmic lipid droplet formation, indicating impaired differentiation. Taken together, these results show that CLA enhances both differentiation and proliferation of bovine intramuscular preadipocytes, possibly via activation of C/EBPα and PPARγ, with GPCR41 playing a critical role in mediating this adipogenic effect.
Non-ampullary duodenal adenocarcinoma (NADA) is a rare malignancy with an incompletely characterised tumour immune microenvironment (TME). We aimed to elucidate its immune niche landscape and validate a clinically applicable transcriptomic surrogate. In 38 resected NADA cases, multiplex immunofluorescence spatial proteomics was performed on tissue microarrays, validated by cohort-wide whole-slide imaging. A 10-gene qRT-PCR panel capturing adaptive immune resistance mechanisms was integrated with spatial data. Molecular microsatellite instability (MSI) testing confirmed mismatch repair (MMR) status in all integrated cases. Spatial proteomics identified seven distinct cellular niches; the immune-active "Hot spot" niche showed a trend toward prolonged survival. The 10-gene panel classified patients into "Hot," "Intermediate," and "Cold" clusters, with the "Hot" cluster significantly enriched in "Hot spot." A pMMR subgroup with abundant "Hot spot" (7/29, 24.1%) was identified, most belonging to the "Hot" cluster (5/7, 71.4%). Molecular MSI testing confirmed all pMMR "Hot" cases as microsatellite stable. External transcriptomic analysis revealed enrichment of interferon-gamma and inflammatory response pathways in the "Hot" group. Spatial proteomics identified an immune-active "Hot spot" niche in NADA. The 10-gene panel serves as a spatial surrogate, identifying a microsatellite-stable pMMR subgroup that may represent a biologically relevant subgroup for future investigation.
Caregiving is a common responsibility in the United States, and about 1 in 5 Americans provide unpaid care for older adults or family members with disabilities. Many adults also provide care for their children. Despite substantial evidence about the potential impact of caregiving on caregivers' mental health, most studies focus on middle-aged adults. Less is known about how caregiving affects the psychological well‑being of young adults, particularly college students. This study examined whether spending substantial time on unpaid caregiving (11 or more hours per week) is associated with greater psychological well‑being among students. The study participants were selected using a probability sample and included students aged 18-30 years who were enrolled at a large public university in Florida. A total of 692 participants completed the 2025 Spring American College Health Association-National College Health Assessment. Overall psychological well‑being was assessed using Diener's Flourishing Scale. Statistical methods included Kruskal-Wallis tests and a generalized linear model with a Gamma distribution, controlling for demographic and academic characteristics. Overall, 3.61% of students reported spending substantial time on caregiving. The overall psychological well-being score (mean and median) was significantly higher among students who spent substantial time on caregiving compared to those who did not (p = 0.0177). The model yielded a similar conclusion (mean difference = 3.82, 95%CI = 1.15:6.49, p = 0.0135) and resulted in additional significant differences in mean scores across several characteristics, including sexual minority status (p < 0.0001) and race/ethnicity (p = 0.0020). Findings suggest that spending substantial time on caregiving is associated with greater psychological well-being among college students. Further research is needed to identify the mechanisms underlying this association and to examine whether these findings generalize to other populations.
The intensification of climate change has led to frequent extreme flooding events, which threaten plant growth and food security. Studying the molecular mechanisms underlying plant flooding resistance is crucial for germplasm improvement. Distylium chinense, a perennial shrub found in the water-level fluctuation zone of the Three Gorges Reservoir, has both strong flooding tolerance and high ornamental value, making it an ideal material for studying plant flooding resistance mechanisms. By integrating multiple sequencing technologies, we assembled a high-quality 917 Mb near telomere-to-telomere genome of D. chinense with a contig N50 size of 73 Mb, representing the first high-quality genome of the Hamamelidaceae family. Whole-genome duplication analysis revealed that D. chinense experienced gamma events that are common to those of core eudicots. In addition, this study revealed three different flooding stress response stages in D. chinense, namely, the acute stress period, the outbreak period, and the long-term adaptation period. Among these, the outbreak period could be an important turning point, during which D. chinense switches from survival mode to adaptation mode. This study also revealed that the expression of the group VII ethylene-responsive factor (ERF-VII) gene g3958 was significantly upregulated under flooding stress and that this gene can be directly activated by the AtWRKY33-homologous gene g19705. On the basis of a comprehensive analysis, a potential dual pathway regulatory model between MKK9 and ERF-VII was further proposed. This study provides important genetic resources for improving flood-resistant germplasms and further contributes to the protection and restoration of the ecosystem in the water-level fluctuation zone of the Three Gorges Reservoir.
This study evaluates the dosimetric feasibility of carbon-ion radiation therapy (CIRT) for ocular melanoma (OM) using a local effect model-I-based treatment planning system (TPS) combined with pencil beam scanning delivery. Cube-shaped targets were designed based on the experience of CIRT for OM at the National Institutes for Quantum Science and Technology (QST). Treatment plans used the local effect model-I-based TPS (Syngo® V13C, SIEMENS, Germany) prescribing an absorbed dose consistent with values reported in the literature. A conversion factor (CF) was established to convert the QST dose to LEM based relative biological effectiveness (RBE)-weighted dose. The physical doses were verified by an in-house Monte Carlo program and measurement. The CF for the LEM, equivalent to the QST RBE-prescribed dose of 70 Gy (RBE) over 5 fractions, was established as 0.65. The 3D gamma passing rate between TPS and MC was ≥94% using 3%-3 mm criteria. Mean dose deviations between the TPS and measurement were ≤±1.61% for all targets sizes except the smallest one (7 mm). Mean distance-to-agreement was <1 mm for all plans except one with a range shifter (distance-to-agreement = 2.92 mm). Phantom cases showed a lateral penumbra of 5.4-6.2 mm, and distal dose fall-off measures 3.6 and 5.6 mm. The results underscore the need for RBE-weighted dose conversion when applying QST's CIRT experience to OM treatment.
Quantum spin liquids (QSL) are prototypical examples of ground states with massive many-body entanglement. While an unambiguous realization of this long-sought-after state remains elusive, a growing number of materials candidates keep emerging with varieties of novel and exotic properties. Here, we report a combined experimental and theoretical study of a new antiferromagnet Ba$_3$CuNb$_2$O$_9$ which has an in-plane anisotropic exchange interaction arising from distorted triangular arrangements of magnetic Cu$^{2+}$ (spin-1/2) ions. We show an unconventional gapless quantum spin liquid (QSL) like ground state in this material which does not exhibit any signature of magnetic ordering down to 0.3 K, while a finite Curie-Weiss temperature $\sim$ - 41 K is evident. The gapless QSL state is supported by a high spin fluctuation, a power-law dependence of magnetic specific heat ($C_m$ $\propto$ $T^{\gamma}$) and a unique scaling of magnetic susceptibility and specific heat with temperature and magnetic field respectively. Our ab-initio simulation also confirms the anisotropic exchange interaction which can only be explained via superexchange mechanism. While the combined results strongly suggest a random singlet state driven QSL behavior in present material, we strongly believe that the anisotropic exchange interaction has a possible role for this exotic ground state behavior.
Simultaneous digestive and metabolic disorders in pregnant dairy cows present significant diagnostic challenges, especially during the dry period when physiological adaptations obscure clinical signs. The concurrent occurrence of left displaced abomasum (LDA), liver abscessation, and traumatic reticuloperitonitis (TRP) is uncommon and highlights the diagnostic challenges associated with non-specific clinical signs during the dry period. A six-year-old Holstein cow, in her fourth lactation and at 276 days of gestation, presented with lethargy, diarrhea, and reduced feed intake. Clinical examination confirmed LDA, while blood biochemistry indicated hepatic dysfunction with elevated gamma-glutamyl transferase (GGT) and aspartate aminotransferase (AST) activities. A right-sided omentopexy was performed; however, the cow's condition deteriorated, requiring an emergency cesarean section. Despite intervention, the animal failed to improve and was euthanized. Postmortem examination revealed a large hepatic abscess (21 cm in diameter) containing approximately 5 L of purulent material, TRP caused by a 4-cm nail embedded in the reticulum, and acute abomasitis. The coexistence of these conditions suggests a possible association between traumatic, inflammatory, and metabolic processes; however, the exact sequence of disease development could not be definitively established. This case highlights the diagnostic complexity of concurrent metabolic and infectious disorders in late-gestation dairy cows. The findings emphasize the importance of early recognition, careful interpretation of clinical and laboratory findings, and comprehensive diagnostic evaluation in dry cows, where physiological adaptations and reduced monitoring intensity may delay detection of severe underlying disease.
Ischemia-reperfusion injury due to vascular pedicle occlusion is one of the most common causes of free flap failure in head and neck cancer reconstruction. Remote ischemic preconditioning (RIPC) has been proposed as an experimental, non-invasive intervention to attenuate flap ischemia-reperfusion injury; however, the tissue-protective mechanisms remain unclear. RIPC may have multiple effects on the inflammatory system, which plays a central part in the pathophysiology of ischemia-reperfusion injury. The aim of the present study was to evaluate the effect of RIPC on inflammatory cytokine plasma levels during free flap reconstruction. Head and neck cancer patients (n = 60) undergoing tumor resection and subsequent free flap reconstruction between August 2015 and November 2017 at Aarhus University Hospital, Denmark were randomized 1:1 to RIPC or sham intervention in a single-center, single-blinded, randomized controlled trial (RCT) (ClinicalTrials.gov: NCT02548377). The study was approved by The Central Denmark Region Committees on Health Research Ethics (journal no. 1-10-72-140-15) and reported following the CONSORT guidelines. RIPC was administered intraoperatively as four 5-min cycles of upper extremity occlusion and reperfusion with an inflatable tourniquet. Blood samples were collected before surgery, 6 h after RIPC/sham intervention, and on the 1st postoperative day. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and interferon (IFN)-gamma were analyzed using a multiplex immunoassay. The average age of the RIPC group was 67 years (±10) and 64 years (±12) in the sham group. Plasma levels of the pro-inflammatory cytokines changed significantly between preoperative measures to 1st postoperative day between RIPC and sham; TNF-α (p < 0.001), IL-6 (p < 0.001), IL-8 (p < 0.001), IL-12p70 (p < 0.001), and IFN-γ (p < 0.001). No significant differences in cytokine levels were shown between groups at any specific time points. RIPC does not attenuate pro-inflammatory cytokine release in head and neck cancer patients undergoing free flap reconstruction. ClinicalTrials.gov identifier: NCT02548377.
Maternal obesity (MO) alters the intrauterine environment and increases the risk of a variety of developmental outcomes; however, the effects on placental cell population and development remain unclear. In this study, we investigated the impact of MO on placental cellular composition, development, and morphology in C57BL/6J mice fed a control or high-fat diet. Single-cell RNA sequencing of embryonic day (E) 13.5 placentas identified 16 transcriptionally distinct cell populations and revealed a reduction in the trophoblast progenitor cell population in MO placentas. MO suppressed trophoblast genes involved in placental development and mitochondrial oxidative phosphorylation, accompanied by decreased protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a key regulator of mitochondrial biogenesis. Furthermore, MO reduced the expression of Hand1 and Tfap2c, transcription factors involved in trophoblast differentiation and placental development, while increasing prolactin-family gene expression and STAT5 phosphorylation. At E17.5, MO caused female-specific reductions in placental weight and labyrinth zone area, along with increased Tnf expression and sustained suppression of Hand1 in female placentas. These findings suggest that MO disrupts trophoblast differentiation and placental metabolic function during midgestation, which may contribute to placental vulnerability later in pregnancy.
To conduct a formal welfare analysis quantifying the economic costs of racial and ethnic disparities in dental care access among Hispanic and non-Hispanic Black, Asian, and multiracial adults relative to non-Hispanic White individuals in the United States. Cross-sectional, observational study using pooled nationally representative data from the 2014 to 2023 Medical Expenditure Panel Survey (MEPS). Two-part models were employed: generalized linear model (GLM) with log link for the probability of any dental visit and generalized linear gamma regression models with log link for modeling visit frequency, total annual expenditures, and expenditure per visit among users. MEPS Full-Year Consolidated Data Files, 2014-2023. The final pooled cross-sectional analytic sample included 205,894 respondents aged 18 and older, representing a survey-weighted annual population of 251,029,718 US adults. Dollar figures are in constant 2023 US dollars. All examined minority groups experienced lower dental care access and higher expenditure per visit compared with White individuals. Estimated aggregate annual welfare losses ranged from $8.23 to $12.93 billion for Hispanics, $6.44 to $9.84 billion for non-Hispanic Blacks, $2.82 to $4.30 billion for Asians, and $1.57 to $2.57 billion for individuals of other or multiple racial identities (total $19.06-$29.64 billion). Dental care disparities persist after adjusting for socioeconomic, demographic, and health characteristics, generating large aggregate welfare losses for minority communities. Addressing provider diversity, cultural competency, and structural barriers is essential to reducing these inequities.
Fetal hemoglobin (HbF) expression is silenced postnatally in adult erythroid cells. Sufficiently increased expression of HbF has been shown to overcome the pathophysiologic sequelae of both sickle cell disease and beta-thalassemia. As the MBD2a-NuRD chromatin remodeling complex is required for silencing of HbF, the present studies were aimed at exploring a potential therapeutic approach for disrupting this complex. AlphaFold 3 and a recent crystal structure were employed to predict the critical interaction domains linking GATAD2A in the histone deacetylase core subcomplex (HDCC) of NuRD and the CHD4 ATPase which has been shown to be required for silencing of the fetal gamma-globin ( HBG ) genes. The two predicted critical domains, the CR2 helical domain of GATAD2A and the C-terminal domains 1 and 2 (C1b and C2ab) of CHD4, were validated by in vitro biophysical studies. Mutation of two amino acids in the CR2 helical domain of the endogenous GATAD2A gene in HUDEP-2 cells resulted in dissociation of CHD4, loss of repressive chromatin over the HBG promoter and ~40% HbF levels compared to < 1% in control cells. Strikingly, enforced expression of a peptide containing the helical portion of the CR2 domain of GATAD2A in both HUDEP-2 cells and primary adult erythroid cells resulted in high levels of HbF, with up to ~75% HbF compared to mutant peptide control level of ~9% in the latter without perturbing erythroid differentiation. These results suggest that targeting the critical interaction domains of GATAD2A and CHD4 with a macrocyclic peptide or small molecule may lead to much needed small molecule therapeutics for sickle cell disease. Association of CHD4 with the HDCC core of the MBD2-NuRD chromatin remodeling complex is required for silencing of HbF expression in adult human erythroid cellsGenetic alteration or enforced peptide expression of a critical helical domain of GATAD2A results in dissociation of CHD4 from the MBD2-NuRD complex and high-level expression of HbF.
Schizophrenia is thought to arise from disrupted postnatal maturation of prefrontal circuits, but the developmental events linking early vulnerability to adult cortical dysfunction remain unclear. Here, we tested whether the primate medial pulvinar, a higher-order thalamic nucleus interconnected with prefrontal cortex, contributes to prefrontal maturation. Bilateral medial pulvinar lesions in neonatal marmosets altered adolescent prefrontal diffusion trajectories and produced adult working memory deficits, the latter of which did not follow comparable lesions in adulthood. Early-life lesioned animals showed reduced thalamocortical input to layer 3 parvalbumin interneurons, diminished prefrontal gamma power, reduced parvalbumin expression, and immature-like physiology in fast-spiking interneurons. These findings reveal a developmental window in which thalamic input shapes prefrontal inhibitory maturation, suggesting that some forms of cortical dysfunction in psychiatric disease originate not in the cortex itself, but in its thalamic inputs.
Intermittent fasting (IF) has emerged as a promising dietary approach with prospective advantages for clinical as well as non-clinical applications. Research indicates that IF enhances insulin sensitivity, facilitates weight reduction and stimulates cellular repair pathways, including autophagy. Physiological adaptations to fasting are reflected in favorable alterations in biomarkers and metabolic processes. This review examines the current evidence on IF by analyzing studies retrieved through schematic searches of the MEDLINE via PubMed database, Embase and ScienceDirect using specific keyword combinations. It focuses on commonly practiced regimens- Time-restricted eating (TRE) (16/8 method), Alternate-day fasting (ADF), the 5:2 intermittent energy-restriction diet and One meal a day (OMAD) approaches and explores their effects on cardiovascular function, metabolic regulation, cognitive performance and longevity. Various IF regimens including the TRE (16/8 method), ADF, the 5:2 diet and OMAD approaches are discussed in relation to their effects on cardiovascular health, cognitive function, metabolic regulation, aging and longevity. While most finding highlight significant health benefits, inconsistencies and methodological limitations are also reported. Mechanistically, IF orchestrates a coordinated metabolic response through modulation of key nutrient sensing pathway such as AMP activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR) and unc-51-like kinase 1 (ULK1). These cascades interact with Sirtuins (SIRT1/3), peroxisome proliferator activated receptor gamma coactivator-1α (PGC-1α) and the transcription factor EB (TFEB) to regulate autophagy, mitochondrial biogenesis, oxidative stress defense and cellular repair. Clinically, these molecular events underpin improvements in glycaemic control, lipid metabolism and inflammatory balance, supporting the therapeutic potential of IF for cardiometabolic disorders, neuroprotection and healthy aging.