Development and structure-guided characterization of a novel ACE2-binding macrocyclic peptide.

Carbon catabolite repression in Gram-positive bacteria, including the recently developed insights.

Multi-omics dissection of a ceRNA-PKS regulatory network underlying lead tolerance in Morchella sextelata.

Fathering is now recognized as influencing children's health, yet the physiological and behavioral pathways linking harsh fathering to men's health-particularly in the context of intergenerational fathering-remain less understood. This study examined the long-term effects of harsh parenting by Generation 1 (G1) fathers during Generation 2 (G2) men's childhood on physical and mental health problems in G2's adulthood, focusing on three potential processes: (a) G2 men's physiological stress regulation reflected in diurnal cortisol patterns, (b) the quality of the G2 men-G3 child relationship, and (c) the sequential mediation of these two processes. Data from three waves of the Midlife Development in the U.S. survey (MIDUS) of 265 G2 men were analyzed using latent growth modeling and structural equation modeling. Results revealed that G1's harsh fathering in childhood significantly increased the risk of G2 men's physical health problems in middle and old adulthood through dysregulated diurnal cortisol patterns, specifically flattened diurnal slopes in early to mid-adulthood, even while controlling for covariates. Neither the direct impact of harsh fathering nor the mediating mechanisms through the G2-G3 relationship were significant. The present findings suggest that the effects of harsh fathering during childhood on adult sons' health are long-lasting, and the stress regulation system may serve as a key underlying mechanism in this relationship. This study highlights the need for evidence-based fatherhood programs aimed at preventing harsh parenting practices. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Lipid-modified membrane-associated proteins can bind reversibly to cellular membranes, and their steady-state localization reflects a balance between membrane-bound and cytosolic pools. For many small GTPases of the Rho and Rab families, this balance is regulated by GDP dissociation inhibitors (GDIs), which control membrane association by shielding the prenyl group and coupling localization to the nucleotide state. In contrast, Ras proteins were long thought to lack a comparable regulatory system. The prenyl-binding protein PDE6D has emerged as a GDI-like factor for prenylated Ras proteins. Here, we discuss the role of PDE6D in KRAS trafficking and spatial organization, and examine its potential as a target for pharmacological inhibition of oncogenic KRAS signaling.

The fabrication of crystalline stimuli-responsive materials with high-contrast and rapid-response behavior and establishing an efficient strategy system for performance regulation are highly appealing for the development of intelligent materials. In this context, four novel multistimuli-responsive functional coordination polymers (CPs), {[Ln(m-bcbp) (NDC)0.5(H2O)1.5(NO3)0.5]·Cl·(NO3)}n (Ln = Eu, CP 1-Eu; Ln = Dy, CP 1-Dy) and {[Ln(m-bcbp) 0.5(NDC) (H2O)2]·Cl}n (Ln = Eu, CP 2-Eu; Ln = Dy, CP 2-Dy), based on viologen ligand and lanthanide ions were successfully prepared and systematically characterized. All CPs exhibit fast and reversible chromic responses under UV irradiation and applied voltage, enabled by the strong electron-donating ability of the electron-rich ancillary ligands, excellent redox activity of viologen, and distinct π-π stacking between them. Moreover, the formation of viologen radicals via photoinduced electron transfer (PIET) confers upon these compounds highly contrasted photomagnetic (30.8% reduction for CPs 1-Dy) and photoluminescent (95.4% quenching for CPs 1-Eu) responses. Furthermore, based on the well-defined crystal structure, the intrinsic coordination flexibility, and the diverse photoresponsive behavior, the performance regulation mechanism was comprehensively elucidated.

Osteoarthritis (OA), the most common degenerative joint disease worldwide, currently lacks effective disease-modifying therapies that can halt its progression. This therapeutic challenge stems from the complexity of multiple pathological mechanisms, including chondrocyte metabolic imbalance, inflammatory responses, and extracellular matrix (ECM) degradation. In recent years, epigenetics, particularly reversible methylation modifications, has provided a new perspective for understanding OA. This review systematically analyzes the multi-dimensional methylation regulatory network in OA from a "pan-methylation" perspective. DNA methylation regulates the transcriptional activity of key genes (e.g., SOX9, MMP13) through the DNMTs/TETs enzyme system. RNA epitranscriptomic modifications (e.g., m6A, m5C, m7G methylation) precisely controls mRNA stability, translation efficiency, and splicing processes via its "Writers-Readers-Erasers" machinery (METTL3, FTO, YTHDFs, etc.), influencing autophagy, inflammation, and metabolic balance. Histone methylation (e.g., H3K27me3, H3K79me2) directly regulates catabolic gene expression by altering chromatin states. These multi-layered methylation networks collectively form a complex epigenetic regulatory system in OA. Based on these findings, targeting specific methyltransferases has shown great therapeutic potential in preclinical studies. This review not only deepens the understanding of OA pathogenesis but also provides a theoretical basis and innovative strategies for developing disease-modifying therapies targeting the methylation network. Future research should focus on joint-specific drug delivery systems and epigenetic precision therapy to promote a fundamental shift in OA treatment paradigms.

Anxiety, for better or for worse.

The plasma membrane proton pump [PM H+-adenosine triphosphatase (PM H+-ATPase)] is essential in plants. C-terminal phosphorylation events regulate proton pump activity, such as Thr881 phosphorylation in Arabidopsis AHA1. We discovered a sequential protein phosphorylation pathway in which two distinct types of Raf-like protein kinases, C5-Raf and C7-Raf, form a heterocomplex that phosphorylates Thr881 to activate PM H+-ATPases. This regulatory system is highly conserved across lineages from liverworts to angiosperms. In Arabidopsis, a C5-Raf Raf36 regulates plant growth through the phosphorylation of multiple Arabidopsis H+-ATPases (AHAs). Additionally, another C5-Raf HT1 functions with C7-Rafs CBC1/2 to phosphorylate AHA1T881, thereby generating a driving force for light-induced stomatal opening. Our findings provide a framework for understanding PM H+-ATPase activation in various physiological processes, particularly in elucidating the complete mechanistic understanding of light-induced stomatal opening.

Building on my 2023 paper, this article revisits countercurrent multiplication (CCM) and makes three advances. First, it presents an enlarged, detailed, classroom-ready diagram that illustrates how the corticopapillary osmotic gradient (OGISF) emerges; and it further refines the previously proposed concept of the NKCC2 activity gradient (AGNKCC2) along the thick ascending limb (TAL) into the NKCC2 transport rate gradient (RGNKCC2), a more inclusive formulation for explaining the formation of the OGISF. Second, it reinterprets ΔOC, the transepithelial osmotic difference across the TAL, as an emergent, system-level outcome produced collectively by many TALs and amplified cycle-by-cycle during CCM. Third, it expands the earlier CCM-equilibrium renal osmoregulation framework by reconceptualizing renal osmoregulation as a highly dynamic and adaptive regulatory system. In this framework, renal osmoregulation operates within a continuously regulated regime punctuated by episodic CCM activation. CCM represents an intrinsic regulatory mechanism that may be activated intermittently to produce transient, step-like increases in urine-concentrating ability when the prevailing regulatory regime alone cannot meet osmoregulatory demand for maintaining body fluid balance. This reframing offers a physiologically plausible account of how renal osmoregulation operates over time. Together, these advances may provide a clearer, classroom-friendly picture of renal osmoregulation and suggest testable ideas for future research.

UPEC's secret weapon: DanRI disrupts immune defense in UTIs.

Methylotrophic yeasts such as Pichia pastoris are widely used for heterologous protein production because they contain strong and tightly regulated promoters. However, the use of methanol as an inducer presents several practical challenges, including toxicity, flammability, high oxygen demand during fermentation, and increased production costs. To overcome these limitations, researchers have been working on redesigning the AOX1 regulatory system and developing alternative induction strategies that do not rely on methanol. One promising approach is optogenetics, which uses light to control gene expression in a non-invasive way. These systems rely on light-sensitive proteins such as phytochromes, cryptochromes, LOV-domain proteins, and UVR8, allowing gene activity to be regulated in a precise and reversible manner without adding chemical inducers to the culture medium. This review brings together key advances in yeast optogenetics, with a focus on the EL222 system, highlighting its implementation for light-controlled heterologous protein production in P. pastoris and its broad application in synthetic biology and metabolic engineering in Saccharomyces cerevisiae. The growing versatility and scalability of EL222-based circuits highlight their potential to reshape both fundamental research and industrial bioprocessing through safer, more controllable, and energy-efficient gene regulation strategies.

The transition away from animal experimentation is gaining momentum across scientific disciplines, driven by technological advancements, ethical imperatives and policy support. At the forefront of this movement is the development of New Approach Methodologies (NAMs). Rather than serving as mere substitutes for animal testing, NAMs represent a paradigm shift. Their growing acceptance has been reinforced by recent policy advancements, such as the US Food and Drug Administration Modernization Act 2.0 and the European Chemicals Agency's commitment to transitioning toward an animal-free regulatory system, both of which promote the adoption of NAMs. However, the term NAMs has become increasingly ambiguous, leading to confusion and potential misuse. To address this, we propose a unified definition: NAMs are species-specific methodologies, not including the use of living animals. NAMs prioritize the use of the target species in some form or another, eliminating the need for interspecies extrapolation. If the target species is human, this simple definition implies that working with experimental animals as a model never qualifies as a NAM. This distinction positions NAMs as a fundamentally different approach to the 3Rs framework of Replacement, Reduction and Refinement, and practical examples are discussed. Critically, this definition extends beyond toxicology and regulatory science, encompassing basic, applied and translational research. By leveraging cutting-edge technologies, including organoids, organ-on-chip, microfluidics, 3D bioprinting, bioinformatics, artificial intelligence and machine learning, NAMs provide novel biological insights that differ from those obtained through animal models while enhancing species-relevant data accuracy. Although challenges remain, particularly in their validation and widespread adoption, continued innovation, policy support and interdisciplinary collaboration will be key to unlocking their full potential, fostering more sustainable, humane and human-relevant approaches in biomedical research.

To evaluate a brief telepsychotherapy service within the Brazilian Unified Health System in a Brazilian capital (April 2024-April 2025), analyzing its functioning, outcomes, and contribution to access in primary health care (PHC). A quantitative descriptive study using secondary data from the service's regulatory system and records. Individuals ≥18 years of age with a therapeutic outcome during the period were included. Descriptive, bivariate (chi-square, Welch's t, and Mann-Whitney), and binary logistic regression analyses were performed. One hundred and ninety-three users participated, predominantly women (88.1%) and adults aged 25-59 years (80.3%). The outcome was discharge in 37.8% and discontinuation in 62.2%. Reasons for discontinuation included absences (30.6%), unsuitability (13.5%), at the patient's request (12.4%), and referral to the psychosocial care center (5.7%). In the regulatory system, "Mental and behavioral disorders" (ICD F00-F99; n = 126) predominated, with frequent use of ICD Z codes, suggesting diagnostic difficulties in PHC. Most teleconsultations occurred in urban units (97.2%), with 77.7% of requests coming from units with multiprofessional teams in primary health care (eMULTI); the average attendance rate was 58.75%. In bivariate analyses, the outcome was associated with the presence of eMULTI (p = 0.0398) and the ICD chapter (p = 0.0056). The attendance rate differed significantly between high-level and low-level attendance (p < 0.0001). Telepsychology is a relevant strategy to expand access and reduce unmet demand in PHC. However, challenges regarding adherence and continuity persist. Effectiveness depends on clear workflows, qualified teams, and engagement and integration strategies between PHC and specialized services.

Bacterial pathogens must overcome oxidative stress to survive within host phagocytes. Although canonical systems such as OxyR are well characterized, alternative pathways remain poorly understood. Here, we identified YchJ, a conserved yet uncharacterized protein, as a central redox-sensitive transcription factor that coordinates a major antioxidant defense system in Salmonella independently of OxyR. Deletion of ychJ severely impaired bacterial survival under H₂O₂ stress and within macrophages. Proteomic analysis revealed that YchJ represses rssB, leading to RpoS accumulation and upregulation of key antioxidant enzymes, including SodC and KatE. Our results show that YchJ directly binds the rssB promoter as a transcription factor. Structural analysis revealed that ROS sensing by YchJ is achieved through reversible dimerization mediated by an intermolecular disulfide bond. This conformational switch enables a C-terminal basic-rich region of the dimer to recognize a palindromic sequence in the rssB promoter and repress rssB transcription. Dual-transcriptome analysis further confirmed that YchJ directly activates antioxidant defenses in Salmonella and significantly disrupts host pathways during intramacrophage infection. Our findings elucidate a previously unrecognized redox-sensing pathway essential for bacterial virulence and uncover a transcriptional mechanism controlling RpoS stability, thereby expanding our understanding of the stress-response regulation system in pathogenic bacteria.

Dissecting gene regulation today relies on many genomic assays - including transcriptional output from RNA-seq, chromatin accessibility from ATAC-seq, and transcription factor (TF) binding from ChIP-seq. Whereas numerous tools exist for each modality and some integrate data across modalities, few allow researchers to interactively explore and visualize how TF binding motifs intersect with transcriptional activity and chromatin accessibility in a tissue-specific context. Here we introduce VIDEO (Visual Integration of Drosophila Enhancer Organization), a web-based analysis tool that enables visualization of conserved TF binding motifs within proximal enhancers of genes differentially expressed in specific tissues. Starting with gene lists derived from in situ hybridization, microarray, and/or scRNA-seq studies of WT or mutant samples, one can identify the TFs expressed in each tissue and learn if and where the consensus binding motifs for those TFs are found within the proximal enhancers of a custom gene set. This pipeline also allows for coincident visualization of active chromatin, as determined from ATAC-seq data, and for the visualization of DNA binding data from ChIP-seq datasets for specific TFs. To demonstrate its utility, we apply VIDEO to the well-characterized regulatory system of CrebA and the secretory pathway in the Drosophila melanogaster salivary gland. We also explore a lesser-known system in the embryonic hindgut to show how utilization of this tool can serve to generate hypotheses regarding regulatory interactions.

Muscle wasting, prevalent in various pathological conditions including cancer, cardiac dysfunction, and neurodegeneration, is typified by sustained protein depletion in muscle and a compromised ability of the tissue to repair and regenerate effectively. Triggered by disruptions in protein folding in the endoplasmic reticulum (ER), the unfolded protein response (UPR) represents a key regulatory system that sustains intracellular proteostasis under conditions of stress. While the UPR is crucial for cellular survival, prolonged activation or dysfunction of the pathway can contribute to muscle atrophy and the progression of muscle wasting diseases. Recent evidence suggests that exercise, through its impact on cellular stress responses, can modulate the UPR in muscle cells, promoting a protective response that enhances protein folding capacity, reduces ER stress, and stimulates muscle regeneration. This review explores how exercise influences the UPR in muscle cells, focusing on the activation of key UPR sensors, including IRE1, PERK, and ATF6, and their downstream effects on protein quality control, autophagy, and muscle fiber maintenance. We also examine the role of exercise in promoting adaptive responses in muscle cells, including increased mitochondrial function, autophagy, and the activation of stress resistance pathways, all of which can counteract muscle wasting. The review also emphasizes exercise as an effective strategy to influence ER stress pathways and attenuate muscle atrophy associated with pathological conditions, offering critical insights into the molecular benefits of physical activity for muscle preservation.

ABSTRACT The widespread application of digital technologies in urban green landscape design has brought new opportunities while introducing cybersecurity challenges. Frequent occurrences of cyber attacks, data breaches, and privacy infringements severely threaten the stability and data security of urban green landscape systems. This study analyzes current applications in spatial thermal energy regulation and urban landscape governance, proposing strategies including thermal energy scheduling coordination, energy storage, optimized scheduling models, fault-tolerant scheduling strategies, and thermal energy regulation simulations. An AI-based urban landscape governance system is constructed, along with an ecological safety assessment methodology for landscapes, along with evaluations of its current status and system architecture. The research particularly focuses on cybersecurity issues, ensuring data security and operational stability through encrypted communication protocols, firewall configurations, vulnerability scanning, and real-time monitoring and early warning of cyber attacks using AI technology. The findings reveal that the AI-powered spatial thermal energy regulation system significantly enhances the stability and ecological security of urban green landscapes. Optimized scheduling effectively reduces urban heat island effects, strengthens internal ecological connectivity, and substantially improves the effectiveness of urban green landscape governance. In terms of cybersecurity, multi-layered protective measures successfully resist various cyberattacks, safeguarding data integrity and operational stability. Practical evidence demonstrates that AI systems integrated with cybersecurity measures exhibit significant advantages in urban green landscape governance.

South Asia bears a high cancer burden, low universal health coverage and high out-of-pocket expenditure. Access to anticancer medicines is challenging and is influenced by determinants-National Essential Medicines List (NEML), registration and local production-yet these are rarely evaluated. This study evaluates these determinants in eight South Asian countries. Multimethod study using a document analysis phase and semistructured interviews. Eight South Asian countries (Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka) for document analysis, with stakeholder interviews conducted in six countries, excluding Bhutan and Maldives. Data were collected from eight regulatory authorities and 30 interviews with drug supply chain stakeholders across six South Asian countries. The inclusion of 67 anticancer medicines from the 2023 WHO Essential Medicines List (EML) into NEML, their registration and local production, along with macrolevel indicators and stakeholders' perspectives regarding them. The median number of medicines included in NEMLs, registered and locally produced was 23.5, 45 and 6.5, respectively. Local production correlated positively with NEML inclusion (ρ=0.884, p=0.004) and negatively with healthcare expenditure (r = -0.732, p=0.039). Three countries listed >50% of the WHO EML medicines on their NEMLs; six had >50% registered. Local production remained limited, with imports dominating supply. Qualitative analysis identified three key barriers to improving availability: financial constraints, a weak regulatory system and insufficient strategic planning. Access to anticancer medicines is constrained by systemic misalignment between NEML inclusion, registration and local production, undermined by weak regulatory coordination, limited strategic planning and financial constraints. Strengthening regulatory coordination, improving registration efficiency and supporting regional production strategies aligned with guided WHO guidance may help improve equitable access to cancer medicines in the region.

Thyroid diseases fall under the category of"goiter, goiter tumor, and goiter qi"in Traditional Chinese Medicine(TCM). The core pathogenesis primarily involves liver qi stagnation, with phlegm coagulation and blood stasis as the clinical manifestations, and spleen-kidney yang deficiency as the root cause. Qi stagnation, phlegm coagulation, and blood stasis interconnect at the cervical liver meridian pathway, accompanied by emotional stagnation, dual deficiency of qi and yin, and alternating cold and heat, constituting a common chronic visceral and meridian dysfunction disorder in clinical practice. Zhiqidao Lingli Moxibustion is grounded in TCM's holistic view and meridian theory, integrating the essence of emotional regulation to innovatively establish a systematic physiotherapy system: "energy oil acupoint massage+graphene energy patch penetration+compound moxa stick medicinal moxibustion+Wuji differentiation tablet precision energy guidance+physician-patient mental resonance+constant-temperature controlled-time deep moxibustion therapy. "This system, based on standardized physiotherapy, adheres to the principle of fixed main acupoints and syndrome-differentiated complementary points, achieving effects of"warm without scalding, penetrating without injury, precise energy accumulation, and mind-body coordination"through standardized procedures. Concurrently, it constructs a tripartite regulation plan combining moxibustion therapy, nutraceutical intervention, and healthy lifestyle correction. Moxibustion is administered in three progressive treatment courses, while nutraceutical intervention employs a fixed foundation of"Ganqing Bao+Changwei Bao+Shenqin Bao"combined with syndrome-differentiated matching, supplemented by lifestyle correction and health exercise guidance. This multidimensional approach addresses core pathogenic mechanisms to achieve regulatory goals such as soothing liver qi and activating blood circulation to resolve stasis. This article systematically explores its academic theory and physiotherapy system, providing comprehensive academic support and practical references for external TCM treatment of thyroid diseases, as well as novel insights for complementary regulation between TCM and Western medicine.