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Bidirectional DC-DC converters are widely used in electric vehicle (EV) powertrains. The adoption of digital control in such converters introduces inherent delays, particularly computational and PWM delays, which influence system stability and dynamic performance. Various delay mitigation techniques have been proposed; however, their impact on the frequency-domain characteristics and transient performance of bidirectional DC-DC converters has not been analyzed. This paper presents a delay-aware frequency-domain analysis of a digitally controlled bidirectional DC-DC converter, relating sampling strategies to effective control delay and corresponding stability margins. An advanced multi-sampling PWM technique incorporating sample-shift is implemented in this topology, and a comparison is carried out with single sampling and conventional multi-sampling. The frequency-domain results show that, in buck mode, the proposed approach improves the phase margin from 60.89° to 68.64° and the gain margin from 35.52 dB to 42.87 dB. Time-domain results support these observations, the settling time is reduced from 0.059 s to 0.038 s, and the steady-state error during input voltage disturbances is reduced from 7.73 V to 4.26 V in buck mode. Similarly, in boost mode, the response time to the reference step change improves from 0.00789 s to 0.00688 s, and the settling time is reduced from 0.0747 s to 0.0732 s. Experimental validation supports the effectiveness of the proposed approach.

Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid decline in glomerular filtration function caused by multiple factors. Factors such as stones and tumors can lead to AKI following renal obstruction. Renal tubular epithelial cell injury is a key component of the pathophysiological mechanism of ischemic acute kidney injury after obstruction.Oxygen-glucose deprivation (OGD) in HK-2 cells and a mouse model of unilateral ureteral ligation (UUO) were used to investigate the role of Claudin-2 in renal tubular epithelial cell apoptosis in ischemia-induced AKI. In animal experiments, the expression of Claudin-2 protein was decreased, while Bax and Caspase-3 expression were increased, and Bcl-2 expression was decreased in the renal tissue of UUO mice. Similarly, after OGD treatment, Claudin-2 protein expression was decreased, Bax and Caspase-3 expression were increased, and Bcl-2 expression was decreased. Upregulation of Claudin-2 protein expression through lentivirus transfection in OGD-treated HK-2 cells reduced the decline in cell viability and the proportion of apoptotic cells. Additionally, upregulation of Claudin-2 protein expression reduced OGD-induced Caspase-3 expression, while the Bax/Bcl-2 ratio showed no significant change. The expression of Claudin-2 is decreased during acute obstructive kidney injury, which contributes to changes in Caspase-3 apoptotic protein and activates cell apoptosis,while the Bax/Bcl-2 ratio showed no significant change.Claudin-2 protein likely modulates apoptosis through a caspase-3-dependent pathway independent of the Bax/Bcl-2 ratio.

Risk stratification in non-ischemic cardiomyopathies (NICM) remains challenging despite guideline-based phenotypic classification using multimodal diagnostics including endomyocardial biopsy (EMB). We aimed to identify EMB-derived histological and molecular markers that improve phenotypic characterization and long-term risk stratification in patients with NICM. In this prospective cohort study, 703 consecutive patients with symptomatic NICM underwent standardized multimodal evaluation, including clinical assessment, cardiac imaging, and endomyocardial biopsy. Biopsy specimens were analyzed using histology, immunohistochemistry, and targeted myocardial mRNA profiling. Associations between endomyocardial markers, and fibroinflammatory remodeling, imaging parameters, and molecular signatures were assessed cross-sectionally. Long-term prognostic relevance was evaluated using survival and multivariable prediction analyses during follow-up of up to fifteen years for all-cause mortality, cardiovascular mortality, implantable cardioverter-defibrillator (ICD) implantation, and appropriate ICD discharge. Elevated myocardial Gremlin-1 expression was associated with increased fibrosis, adverse cardiac remodelling, reduced left ventricular function, and enrichment of pro-fibrotic and inflammatory mRNA signalling pathways. Myocardial and circulating Gremlin-1 expression was independently associated with all-cause and cardiovascular mortality, and ICD implantation and discharge. Machine learning-based phenotyping using histological EMB data identified Gremlin-1 as a key predictive feature of poor prognosis. Incorporation of Gremlin-1 into predictive models significantly improved long-term cardiovascular risk stratification in NICM patients. Our results unveil that Gremlin-1 is associated with inflammation and cardiac remodelling in patients with NICM, and patients with Gremlin-1+ EMB and high plasmatic Gremlin-1 concentrations are at elevated risk to develop adverse cardiovascular events. Thus, the histological evaluation of Gremlin-1 may help to improve risk discrimination and management of NICM and HF patients. Non-ischemic cardiomyopathy (NICM) refers to diseases in which the heart muscle becomes abnormal and unable to pump effectively, without being caused by blocked coronary arteries. Predicting which patients will develop serious complications remains difficult using current clinical tests. We examined whether information from small heart tissue samples could improve long-term risk prediction. We analysed 703 NICM patients who underwent comprehensive clinical assessment and endomyocardial biopsy. Heart tissue was assessed for markers of inflammation and scarring, including the protein Gremlin-1, and patients were followed for up to fifteen years for major cardiovascular outcomes. Higher Gremlin-1 expression and circulating Gremlin-1 were associated with scarring, reduced heart function, and increased risk of adverse outcomes. These findings suggest that tissue-based biomarkers including Gremlin-1 may support more accurate risk stratification and personalized management in NICM.

Globally, pine forest ecosystems are under increased threat of foliar fungal pathogens. This includes brown spot needle blight (BSNB), caused by Lecanosticta acicola. High disease severity of BSNB has been observed in loblolly pine plantations across the Southeastern U.S., causing substantial declines in productivity. Because foliar disease outcomes depend on phyllosphere community interactions, shifts in community composition under climate variation may influence outbreak potential of L. acicola. To investigate these interactions, fungal communities in first- and second-year symptomatic and asymptomatic needle tissue were examined over two years across six loblolly pine plantations in central Louisiana. L. acicola was consistently enriched in symptomatic needles and emerged as a strong indicator of disease, including increasing crown dieback, particularly in first-year needles. Disease progression was associated with reduced fungal diversity and pronounced shifts in community composition, consistent with microbiome dysbiosis. Additional fungi, including Lophodermium and Soleella, were enriched in symptomatic needles, likely representing opportunistic associates with a potential role in disease. There were distinct differences in the relationship with climate variables for symptomatic and asymptomatic communities. Symptomatic communities were associated with higher humidity, higher minimum temperatures, and reduced solar radiation, whereas asymptomatic communities were correlated with warmer, drier conditions. Our findings demonstrate that BSNB severity reflects both L. acicola infection and broader needle fungal community disruption, with first-year needles being especially vulnerable. These results underscore the need to integrate microbial community dynamics and climate into disease monitoring and management, as increasing humidity, warmer nights, and more variable precipitation likely elevate fungal pathogen risk.

Training in neurosurgery is increasingly challenged by the complexity of cranial anatomy, the rarity of certain pathologies, ethical constraints on cadaveric dissection, and limited operative exposure. Advances in three-dimensional (3D) printing have enabled the development of patient-specific anatomical models derived from computed tomography and magnetic resonance imaging, offering realistic, reproducible platforms for surgical training and preoperative planning. This chapter reviews contemporary applications of 3D-printed, hybrid, and multimodal simulation models in neurosurgical education, with particular emphasis on complex craniofacial and encephalocele procedures. Through illustrative case reports-including frontoethmoidal and transsphenoidal meningoencephaloceles, metopic craniosynostosis, and late encephalocele correction-the chapter demonstrates how multimaterial 3D-printing, hybrid silicone-resin constructs, and integration with augmented and mixed reality can enhance spatial understanding, tactile feedback, and procedural rehearsal. Evidence from these cases indicates that patient-specific simulation can alter surgical strategy, reduce operative time and blood loss, and improve multidisciplinary communication. Educational benefits extend beyond surgeons to trainees and allied health professionals, supporting structured skill acquisition and competency-based assessment. The chapter also discusses the relevance of low-cost 3D-printing solutions for low- and middle-income countries, highlighting open-source software and affordable fabrication techniques as tools to reduce global disparities in neurosurgical care. Limitations related to cost, material fidelity, imaging quality, and technical expertise are addressed, alongside future directions for research and curriculum integration. Overall, 3D-printed and hybrid simulation models represent a transformative approach to neurosurgical training and patient-specific surgical planning, with significant implications for education, safety, and global health equity.

Tungsten disulfide (WS2) nanoparticles are widely considered as promising solid lubricant additives for boundary/mixed lubrication. However, the consistent mechanism linking macroscopic tribotests to atomistic behavior remains elusive. We investigated WS2-dispersed polyalphaolefin (PAO 6) lubrication using ball-on-disk experiments, post-test surface analysis, and nonequilibrium molecular dynamics (MD) simulations. The addition of WS2 markedly reduced and stabilized friction, with the average coefficient of friction (COF) decreasing from 0.146 to 0.055, and mitigated wear, with the measured wear volume decreasing from 0.019 to 0.011 mm3 (≈ 42.1% reduction). X-ray photoelectron spectroscopy of the worn surface displayed W 4f and S 2p signals, consistent with WS2-derived species remaining within the wear track after sliding. MD simulations provided a mechanism-level atomistic interpretation consistent with this macroscopic friction trend: the WS2-containing interface exhibited a lower interfacial shear response than the PAO-only interface (time-averaged COF: ≈10.9% reduction from 0.46 to 0.41), while interfacial energetics indicated weaker PAO coupling with WS2 than with Fe (- 101.42 vs. -244.51 eV). This weaker PAO-WS2 coupling suggests that WS2-derived interfacial species may reduce effective PAO-Fe coupling and facilitate lower-shear interfacial accommodation, which is consistent with the experimentally observed friction stabilization and wear reduction. Representative MD configurations also displayed Fe atom detachment in the PAO-Fe model but not prominently in the WS2-mediated case.

Delays in diagnostic confirmation remain common in young children with autism spectrum disorder (ASD). These delays are particularly concerning for children with severe symptoms and elevated support needs, for whom early identification is especially important. There is therefore a need for objective and feasible approaches to assist early identification prior to specialist evaluation. Eye-tracking is a non-invasive method for quantifying gaze-fixation patterns associated with ASD. The present study examined whether gaze-fixation indices derived from the Gazefinder eye-tracking system can identify a clinically defined severe ASD subgroup within a real-world clinical population. The analysis included 442 children aged 2-6 years referred to a child psychiatry outpatient clinic who underwent Gazefinder assessment. Based on Childhood Autism Rating Scale (CARS) scores, children were classified into a Severe ASD group (n = 42) and an Other group (Non-ASD and Mild-to-moderate ASD; n = 400). Gaze fixation rates on predefined regions of interest were compared, and discriminative performance was evaluated using receiver operating characteristic analyses. Children in the Severe ASD group exhibited reduced fixation on the mouth region in dynamic facial stimuli and reduced fixation on people relative to geometry. A composite criterion derived from four gaze-fixation indices yielded a sensitivity of 85.7% and a specificity of 55.3% for discriminating Severe ASD. These findings suggest that Gazefinder-based measures may provide adjunctive information to support screening and referral-related decision-making for clinically defined severe ASD in young children.

The increasing traffic volume and vehicle load, combined with the impacts of climate change, have intensified common types of pavement distress such as fatigue cracking, moisture damage, and rutting in Hot Mix Asphalt (HMA). In this study, the use of reclaimed asphalt pavement (RAP) was investigated as a sustainable approach to reduce HMA production costs while minimizing environmental impact and promoting sustainable development. To enhance the performance of RAP-based mixtures, Nano-Calcium Oxide (CaO) was incorporated into HMA containing 50% RAP at three different dosages: 0.5%, 1%, and 2% by weight of bitumen. A series of laboratory tests were conducted, including fatigue tests at 5 °C and 25 °C, moisture susceptibility tests at 25 °C, and wheel tracking tests at 40 °C and 60 °C. The results indicated that incorporating 50% RAP without Nano-CaO led to an approximately 80% reduction in fatigue life, a 20% reduction in moisture resistance (TSR), and a 60-65% increase in rutting compared to the control mix without RAP. However, the inclusion of 1% Nano-CaO in the 50% RAP mixture significantly improved performance, showing an approximately 94% increase in fatigue life, a 43% improvement in moisture resistance, and a 50-55% reduction in rutting compared to the RAP mixture without Nano-CaO. When compared to the control mixture (without RAP or Nano-CaO), the modified mix containing 50% RAP and 1% Nano-CaO exhibited a 15-20% improvement in fatigue life, an 19% increase in moisture resistance, and a 20-25% reduction in rutting resistance. These findings suggest that the addition of 1% Nano-CaO to HMA with 50% RAP can effectively compensate for performance losses while reducing the demand for new aggregates by approximately 50% and the need for virgin bitumen by about 2.9%, contributing both to performance enhancement and material sustainability.

Tumor-infiltrating nerves play critical roles in promoting tumor growth and progression; however, the mechanisms that drive tumor innervation remain unclear. Upon transformation, tumors recruit surrounding peripheral nerves into the tumor microenvironment (TME) to obtain their own innervation, a process called axonogenesis. While in vitro studies suggest tumor cell-derived neurotrophins, such as brain-derived neurotrophic factor (BDNF), drive axonogenesis, this has yet to be demonstrated in vivo. During wound healing, macrophages are the primary source of neurotrophins. Given the critical role of macrophages in breast cancer growth, we investigated whether these immune cells drive tumor axonogenesis in breast tumors in vivo. Syngeneic Py230 mouse triple-negative breast cancer (TNBC) cells were transplanted into intact mice and mice lacking immune-derived BDNF. Bone marrow-derived macrophages from either wild-type or immune-BDNF-deficient mice were transplanted into tumor-bearing recipients to determine if macrophage-derived BDNF was sufficient to restore tumor growth and innervation. We found that transplanted TNBC cannot grow in the absence of immune-derived BDNF, and that depletion of macrophages from the TME compromises tumor innervation. Remarkably, the introduction of wild-type macrophages restores tumor growth and innervation in mice lacking immune-derived BDNF, demonstrating that macrophages are both necessary and sufficient for tumor axonogenesis in vivo. In the absence of sensory tumor innervation, tumor growth was significantly reduced. Moreover, targeting BDNF signaling diminished TNBC growth and innervation. Our findings identify macrophages as the critical source of BDNF driving axonogenesis in breast cancer and suggest that selectively targeting BDNF signaling could provide a novel therapeutic strategy for treating TNBC through compromising tumor innervation.

Carriers of CYP2C19 loss-of-function (LOF) alleles have reduced clopidogrel bioactivation, higher on-treatment platelet reactivity, and more recurrent ischaemic events. Smoking may enhance clopidogrel responsiveness. We evaluated whether smoking modifies the impact of LOF alleles on clopidogrel effectiveness after acute ischaemic stroke. This is a post-hoc analysis of the PLATELET trial (ClinicalTrials.gov NCT04072705), a prospective, observational study enrolling participants from September 2019 to March 2023. Patients receiving clopidogrel were classified as current or non-current smokers and stratified by CYP2C19 genotype (carriers of LOF alleles vs. non-carriers). The primary outcome was a 6-month composite of ischaemic or haemorrhagic stroke, myocardial infarction, or cardiovascular death. Secondary outcomes included ischaemic stroke, transient ischaemic attack, coronary revascularization, early neurological deterioration and a good functional outcome, defined as modified Rankin Scale (mRS) score 0-2 at 3 months. Safety outcomes were major bleeding and mortality. Among 2,910 participants, the primary outcome occurred in 4.8% of non-current smokers and 4.2% of current smokers. In current smokers, events were lower in non-carriers than carriers (0.6% vs 6.5%), but not in non-current smokers (4.4% vs. 5.0%). In multivariable analysis, non-carriers had a lower risk than carriers of LOF alleles only among current smokers (adjusted hazard ratio [aHR], 0.13; 95% CI; 0.02-0.70). Among the secondary outcomes, only ischaemic stroke showed lower incidence in non-carriers within the current smoking group (0.3% vs. 2.8%), with a significantly reduced risk (aHR, 0.15; 95% CI 0.03-0.85). Safety outcomes did not differ by genotype in either group. The benefit of clopidogrel was confined to current smokers who were non-carriers, with comparable safety. Combining smoking status with CYP 2C19 genotyping may help personalize antiplatelet therapy.

Alpha-synuclein (αSyn) inclusions are a defining neuropathological feature of Parkinson's disease, but the cellular events that initiate their formation and promote neurotoxicity remain incompletely understood. Aberrant liquid-liquid phase separation has emerged as a potential early step in αSyn dysregulation, yet the physiological triggers and functional consequences of this process are unclear. Here, we show that lipid droplets promote the spontaneous phase separation of wild-type and E46K mutant αSyn into condensates. These condensates sequester lipid droplets and impair their turnover, indicating disruption of cellular lipid homeostasis. Mitochondria in close proximity to αSyn condensates exhibit reduced membrane potential and increased mitophagy. Correlative light and electron microscopy further reveals αSyn oligomers associated with mitochondrial membranes displaying structural abnormalities. Together, these findings identify lipid droplets as drivers of aberrant αSyn phase separation and suggest that lipid droplet-rich condensates contribute to mitochondrial dysfunction and impaired energy homeostasis. Given the enrichment of lipid droplets within neuromelanin-containing dopaminergic neurons of the substantia nigra, this mechanism may be relevant to the selective neuronal vulnerability observed in Parkinson's disease.

Microglia contribute to detrimental neuroinflammation under pathological conditions and thereby drive the pathogenesis and development of various diseases of the central nervous system (CNS). Here, the deubiquitinating enzyme OTUB1 is identified as a regulator of microglial activation and CNS inflammation. In mice, microglia-specific OTUB1 deletion significantly ameliorates ischemic brain injury by reducing the pro-inflammatory activation of microglia. OTUB1 enhances Toll-like receptor (TLR) signaling through stabilizing UBC13 and TAB2, leading to the increased induction of cytokines. Notably, OTUB1 reduces the proteasomal degradation of TAB2 by reducing its K48 ubiquitination in a catalytic activity-independent manner. Moreover, microglia-confined OTUB1 deficiency also alleviates lipopolysaccharide-induced sickness behavior and experimental autoimmune encephalomyelitis in mice due to decreased neuroinflammation. Pharmacological inhibition of OTUB1 significantly mitigated ischemic stroke injury in mice. These findings reveal an important role of OTUB1 in potentiating microglial activation and neuroinflammation, providing a proof-of-principle observation for targeting OTUB1 in the treatment of TLR-associated neuroinflammatory diseases.

The aim of this pilot study was to develop and administer a novel parent-report metric, the EZ-chEW, for documenting the temporal characteristics of jaw performance during chewing across various consistencies. We hypothesized that parents could collect data in their home environment and that toddlers would exhibit age- and consistency-related characteristics consistent with prior kinematic research. The development of the EZ-chEW questionnaire was informed by a review of the literature on chewing development, focusing on temporal aspects of chewing. Full-term children participated in chewing trials at 12, 18, 24, and 30 months. Parents reported on three trials per timepoint, and data were categorized into consistency groups using consensus scoring. Sixty-seven toddlers participated longitudinally. Parents completed home data collection with minimal instruction and no direct assistance. Chewing duration (seconds) and the number of cycles (i.e., mandibular open/close cycles) varied by age (p = .001 and p = .035, respectively) and by food consistency (both p < .001), with more complex consistencies generally requiring longer chewing durations and more chewing cycles across all ages. Chewing efficiency (cycles/sec) remained relatively stable across ages (p = .238) but differed by consistency, with more complex foods resulting in higher cycles/sec values p = .028). Parental assessment of chewing performance offers a valuable supplement to clinical evaluations of oromotor function. By capturing naturalistic behaviors in a home setting, EZ-chEW reduces the burden on healthcare providers and families while providing insights into chewing performance. These findings highlight the potential of EZ-chEW as an accessible tool for guiding interventions tailored to the needs of toddlers and their families.

Internet of things (IoT) is a distributed connection of smart objects which collects the data or information from the deployed environment and communicates the data to other devices with Internet as a backbone. Due to its unfriendly deployment nature and openness in communication via Internet, IoT is vulnerable to various types of attacks during data transmission. Intrusion Detection System (IDS) is an effective method to provide strong and efficient security to IoT devices. IDS is a software that tracks the network traffic and identifies the anomalies and abnormal activities. An Improved Ant Colony Optimization (IACO) algorithm with mutual information is proposed which effectively identifies the features in the given dataset and ranks. Moreover, for classification a Hybrid Fuzzy Genetic Algorithm (HFGA) is proposed to identify various types of attacks in the network. The proposed classifier comprises two layers namely external and internal. The external layer generates fuzzy sets and internal layer generates fuzzy rules. In the proposed system during training phase the External Fuzzy Genetic Algorithm (EFGA) helps Internal Fuzzy Genetic Algorithm (IFGA) and the finest individual from EFGA is associated with the fragile individual from IFGA to produce a new output which enhances the estimation of mutated attacks. The performance of the proposed system is evaluated using NSL-KDD dataset. Most of the existing IDS in IoT suffers from lower Intrusion detection accuracy, false alarm rate and has high computational and communication overhead. From the result, the proposed system has achieved better intrusion accuracy and reduced the false alarm rate in the network. Moreover, the proposed system identifies both known attacks and unknown attacks in the network.

Pulmonary fibrosis (PF) remains a lethal progressive disease with poorly defined molecular drivers. Epithelial dysfunction and metabolic reprogramming contribute to PF, but the mechanistic link between these processes remains unclear. Here, we identify a Kat5-STAT6 epigenetic-metabolic axis that governs fibrotic progression. Kat5 directly acetylates STAT6 at lysine 636 (K636), thereby suppressing STAT6 dimerization, phosphorylation and nuclear translocation. In fibrotic lungs, STAT6 acetylation at K636 is reduced, leading to its hyperactivation. Activated STAT6 drives transcription of pro-glycolytic enzyme hexokinase 2 (HK2), promoting metabolic reprogramming in alveolar type II (ATII) cells and extracellular matrix deposition. ATII cell-specific restoration of Kat5 rescues STAT6 acetylation, normalizes its activity and ameliorates fibrosis in vivo. Mechanistically, Kat5-mediated STAT6 acetylation functions as a biochemical brake that limits cooperation with profibrotic mediators such as tissue plasminogen activator (tPA). These findings redefine STAT6 regulation, highlight an acetylation-phosphorylation checkpoint controlling fibrogenesis, and suggest that Kat5 enhancers or STAT6 acetylation mimetics may represent potential therapeutic strategies for chronic lung disease.