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Regenerative medicine is a dynamic, multidisciplinary area aimed at repairing and restoring the function of tissues and organs, incorporating diverse strategies like tissue engineering, bone regeneration, wound healing, and immunomodulation. In this field, biomaterials with exceptional physicochemical and biological properties-such as medical-grade metals, bioceramics, and polymers-play a crucial role. Among these, polydopamine (PDA) stands out as a highly promising material due to its straightforward synthesis, excellent biocompatibility, robust adhesive properties, ease of functionalization, high photothermal (PT) efficiency, and quenching capabilities. These qualities have sparked significant interest in PDA for regenerative medicine, where it acts as a versatile platform for surface modification, facilitating the development of multifunctional nanomaterials with extensive biomedical applications. This review offers a detailed examination of recent progress in PDA research, covering its synthesis processes, physicochemical properties, nanostructured forms, and diverse applications in regenerative medicine. Additionally, it critically assesses current challenges and provides insights into the future development of PDA-based nanoplatforms.

Many valuable plant metabolites are synthesized by type III polyketide synthases (PKS) that have become targets for the engineering of microbial production systems of these compounds. The rhizomes of turmeric ( Curcuma longa ) and ginger ( Zingiber officinalis ) are highly regarded for medicinal and culinary purposes and are the sources of bioactive curcuminoid and gingeroid polyketides. Fast growing demand for these compounds has sparked effort to identify their biosynthetic pathways to facilitate their heterologous production. In turmeric, a collaborative diketide synthase (DCS) and PKS (CURS) pair synthesizes curcumin from feruloyl- and malonyl-CoA. Yet, bona fide genes for the biosynthesis of gingeroids in Ginger are not known. Here we report the identification of two DCS/PKS pairs in Ginger that have different activity profiles in E. coli engineered to provide feruloyl- and hexanoyl-CoA as substrates. We show that one PKS (ZoPKS2) makes 6-dehydrogingerdione (6-DHG) as its major product while the other PKS (ZoPKS1) is a curcumin synthase. We found that Zo PKS2 becomes an efficient curcumin synthase when hexanoyl-CoA is not available, making it a dual-function enzyme that can be used to easily switch heterologous productions towards either of these two valuable products. Precursor feeding studies show that the substrate promiscuity of the collaborative DCS/PKSs may be exploited to access different dehydrogingerdione derivatives, while structural models of the Ginger PKSs offer insights for future engineering of product profiles. We believe that this work will add to the type III PKS toolbox and enable the development of efficient production platforms for gingeroids.

Palladium, as a member of the precious platinum group metals and a strategic resource, exhibits uneven global distribution and price volatility. This has sparked significant interest in its efficient recovery technologies. To tackle the challenge of highly selective Pd2+ recovery and Pt/Pd separation under extreme conditions, we developed a covalent organic framework (COF) adsorbent enriched with pyridinic nitrogen and carboxyl groups, synthesized via one-pot Povarov and Doebner multicomponent reactions. Intriguingly, the incorporation of multiple binding sites within the COF framework significantly enhances Pd2+ interactions, enabling rapid recognition and efficient Pd2+ extraction under highly acidic and simulated high-level radioactive conditions. The as-synthesized site-enriched COF (PQCOF-2) exhibits the highest Pd2+ adsorption capacity of 376 mg g-1 in 3 M HNO3 and achieves a Pt/Pd separation factor of 4.10. Further, PQCOF-2 showed an exceptional Pd2+ distribution coefficient (Kd = 6.79 × 105 mL g-1) and removal efficiency exceeding 99% in simulated high-level radioactive waste solutions, together with notable recovery ability. In brief, this work provides a versatile example for developing advanced adsorbents aimed at capturing radioactive metal ions.

The growing interest in the hydrogen economy has sparked renewed interest in proton exchange membrane fuel cells (PEMFCs); however, the high cost and limited supply of noble metals like platinum remain a major obstacle to their widespread use. A primary bottleneck is the electrochemical oxygen reduction reaction (ORR) owing to its complex, multi-intermediate pathway constrained by fundamental scaling relationships that limit the performance of even the most effective catalysts. Herein, we argue that interfacial heterogeneity, integrating symmetry-breaking perturbations that span the subsurface lattice, the chemisorption layer, and the near-interface solvation volume, provides the mechanistic basis for decoupling the adsorption energetics of ORR intermediates and overcoming these linear scaling relationships. This outlook critically examines recent strategies pursued to this end, including strain engineering, atomically dispersed sites, doping, interfacial field effects, and confinement, that modulate intermediate energetics to varying degrees, yet full thermodynamic decoupling remains elusive in practice. We, therefore, contend that the most promising path forward lies in engineering the interface holistically, integrating the lattice, chemisorption, and solvation contributions rather than tuning any one in isolation, while co-optimizing for durability and transport dynamics in order to translate these mechanistic insights into practical PEMFCs.

Formaldehyde (FA) is a widely used chemical with known carcinogenic properties, particularly for the upper respiratory tract. Concerns about probable FA-induced hematotoxicity and leukemia have sparked investigations into its health risks. This review scrutinized the quality of exposure evaluations in studies exploring the hematotoxicity of FA and assessed the association between FA exposure and blood dyscrasias. A total of 22 studies were included in the systematic review; among them, 10 provided sufficient data for meta-analysis. FA exposure was significantly associated with changes in blood parameters, including white blood cells (standardized mean difference [SMD] = -1.450 ± 0.636), T cytotoxic cells (SMD = 2.813 ± 1.013), and natural killer (NK) cells (SMD = 1.911 ± 0.775). None of the other blood parameters were significantly affected. However, because of inconsistencies and limitations in exposure assessment methods across the reviewed studies, a clear dose-response relationship could not be established. Overall, changes in some blood parameters were possibly a response to the sensory irritation of FA in the upper respiratory tract. Based on the available scientific evidence, inhaled FA is not distributed beyond portal-of-entry to distal tissues or organs. It is recommended that the exposure of workers to FA be evaluated in a more comprehensive way by following well-validated FA sampling and analysis methods in future studies to better elucidate the association between FA exposure and hematotoxicity. Also, biological monitoring is recommended to estimate overall worker exposure to formaldehyde and to assess the association between FA exposure and its probable hematotoxicity.

This research investigates the "Crisis of Sensibility" inherent in modern malestream masculinity, framing it through the ecofeminist lens of the "logic of domination"-a patriarchal framework that reduces the living world to a mere backdrop for human achievement and extraction, while justifying the dual subordination of nature and "others." By synthesising Hultman and Pulé's ADAM-n model of Masculine Ecologisation (the structural roadmap) and Baptiste Morizot's Sensory Ethology (the somatic toolkit), the paper proposes the Etho-ADAM-n model. This analytical synthesis provides a framework for men attempting to exit the 'machine' of Industrial/Breadwinner Masculinity-an identity defined by an "illusion of control" and "crude aggressiveness." The study uses two South Indian films to illustrate this transformation. Through a descriptive cinematic analysis of the films Malayankunju (2022) and Kadaisi Vivasayi (2022), the study tracks how film form facilitates a sensory re-engagement with the biotic community. Rather than presenting a resolved ethical state, the research identifies these narratives as fragile thresholds of vulnerability sparked by environmental rupture and agrarian precarity. Ultimately, the transition models a shift from patriarchal mastery towards a precarious state of ecological belonging.

The growing demand for multifunctional bioactive peptides has sparked interest in underutilized marine by-products as sustainable bioresources. This study explored Alaska Pollock (Gadus chalcogrammus) milt protein as a novel source of peptides with anti-inflammatory, anti-hypertensive, and anti-diabetic effects. Protein composition was analyzed via LC-MS, followed by in silico digestion and bioactivity prediction. Molecular docking identified peptides targeting DPP-IV, α-glucosidase, ACE, GLP-1 receptor, COX-2, MuRF1, and the 20S proteasome. Among the candidates, a promising peptide (CLPPH) was synthesized and validated in vitro, demonstrating inhibitory effects on nitric oxide production, DPP-IV, ACE, and α-glucosidase. These results highlight CLPPH's potential as a multifunctional bioactive peptide and support the valorization of Alaska Pollock milt as a sustainable source for functional foods and nutraceutical applications.

Older adults hospitalised for acute illness are highly vulnerable to functional decline, often exacerbated by inactivity. Although exercise interventions may reduce this risk, uncertainty remains regarding how such programmes should be designed and tailored for frail patients. Embedded within the PREV_FUNC randomized controlled trial, this study explored older patients' experiences of two in-hospital exercise programmes. This qualitative study was conducted at a geriatric hospital in Stockholm, Sweden. Using an inductive approach within a constructivist paradigm, semi-structured interviews were conducted with 24 patients aged ≥ 75 years who had participated in either a comprehensive or a simple exercise programme. Data were analysed inductively using reflexive thematic analysis. One overarching theme emerged: Structured exercise disrupted inactivity and sparked hope for a turning point. This theme comprised four subthemes: Exercise awakens hope for improvement; Getting out of bed can be challenging; Overall confidence in structured exercise; and Support from the physiotherapist is crucial. From the patients' perspective, the exercise programmes helped break periods of inactivity and fostered hope for recovery. These findings suggest that in-hospital exercise may support physical activity in geriatric wards, although individual adaptation and support remain essential.

Synergizing reticular materials to form heterostructures has sparked increasing interest in diverse fields. Organic photoelectrochemical transistor (OPECT) has been demonstrated as a transformative platform for next-generation biosensors, optoelectronics, and neuromorphic simulation. Herein, covalent organic frameworks (COF)-on-hydrogen-bonded organic frameworks (HOF) heterojunction as a novel photogating module is first explored for competitive OPECT biosensing of streptomycin (STR) via a self-assembled protein network. The competitive binding by STR in the solution and on the surface can cause the variant coverage of protein network on the COF-on-HOF photogate, leading to the different steric hindrance with differentiable OPECT responses and thus achieving sensitive STR detection down to 0.5 pM. This work features competitive OPECT biosensing photogated by a reticular heterostructure.

In 2022, the case of Andrea Prudente, an American tourist denied an abortion for a non-viable pregnancy in Malta, catalysed unprecedented social mobilisation, and compelled a legislative review of the country's abortion ban. This paper traces the political and social dynamics that shaped this process, from the initial advocacy to the final, heavily contested legislative outcome. Drawing on Morgan and Roberts' concept of reproductive governance, we examine media content and parliamentary discourses to trace how state actors mediated the conflict between competing moral, and legal frameworks. Our analysis demonstrates that while persistent pressure by pro-choice advocates was instrumental in forcing a legislative review, the government's initial proposed reforms were systematically contested, and ultimately neutralised by a powerful, well-organised anti-choice countermovement. We argue that state actors ultimately capitulated to immense conservative pressures from influential religious and civil society actors. The resulting amendment, which permits termination only under exceptionally restrictive circumstances to save a pregnant person's life, is a stark example of how reproductive governance can accommodate pressure for change while leaving the underlying system intact. This process highlights how legal reform can be critically decoupled from meaningful access, failing to secure genuine reproductive rights. Despite its profound limitations, the amendment constitutes the first-ever legal exception to Malta's absolute ban, proving that such entrenched governance frameworks are not immutable. The Prudente case and the mobilisation it inspired have irrevocably fractured the previous politico-legal consensus, thereby creating a precedent for future legal challenges and continued advocacy for comprehensive reproductive justice in Malta. In 2022, an American tourist in Malta named Andrea Prudente needed an abortion for a pregnancy that could not survive. Doctors refused because of the country's total ban. Her case sparked major protests and forced the Maltese government to review its abortion law. This paper studies how this process unfolded. We looked at newspapers and political speeches. We wanted to understand the arguments of those fighting for abortion rights and those against them. We found that those fighting for abortion pushed the government to act. But a powerful and well-organised anti-choice movement fought against any changes. The government gave in to pressure from influential conservative and religious groups. The result was a new law that is very restrictive. It only allows an abortion in rare cases to save the pregnant person's life. This change does not provide meaningful access to abortion care. Yet, this is the first time there was a change to Malta's complete ban. This shows that the old rules can change. It creates an important starting point for future work to secure full reproductive rights in Malta.

Sparked by innovations in generative artificial intelligence (AI), the field of protein design has undergone a paradigm shift with an explosion of new models for optimizing existing enzymes or creating them from scratch. After more than one decade of low success rates for computationally designed enzymes, generative AI models are now frequently used for designing proficient enzymes. Here, we provide a comprehensive overview and classification of generative AI models for enzyme design, highlighting models with experimental validation relevant to real-world settings and outlining their respective limitations. We argue that generative AI models now have the maturity to create and optimize enzymes for industrial applications. Wider adoption of generative AI models with experimental feedback loops can speed up the development of biocatalysts and serve as a community assessment to inform the next generation of models.

Practice education is an essential component of occupational therapy programmes in Australia, providing supervised opportunities for students to develop skills across diverse practice settings. Rising student enrolments have intensified pressure on universities to secure sufficient practice education opportunities, prompting exploration of alternative models and emerging settings. The research setting, with supervision provided by occupational therapists working in research roles, presents a promising but under-utilised option for practice education. This study aimed to explore the perspectives and experiences of occupational therapy and physiotherapy students, practitioners, and university educators on placements in a research setting. Semi-structured interviews (n = 30) were conducted with occupational therapy and physiotherapy students, practitioners with experience working in research-specific roles, and university educators. The Theoretical Domains Framework guided the development of the interview schedules. Participants were recruited using purposeful and snowball sampling. Data were analysed thematically. The interview schedule was developed in consultation with research practitioners and university educators. Practice education is occurring within research settings, though it is not yet common, with generally positive perceptions reported among those involved. Participants viewed these placements as an opportunity to strengthen research confidence, develop research readiness, and generate interest, alongside meeting core placement competencies. For some participants, practice education in a research setting was a new concept. University educators questioned whether all research settings could satisfy accreditation requirements. Seven themes were identified: research confidence, professional responsibility, sparking interest, missed opportunity, accreditation requirements, fear of missing out on client contact, and risks to the research quality. Utilisation of the research setting for practice education may strengthen students' understanding of how evidence is generated and translated into practice, helping to address persistent concerns about low research confidence and engagement. Effective implementation will require collaboratively developed models that reflect the needs of all stakeholders. Ongoing trial and evaluation are essential to determine feasibility, educational value, and impact. Practice education or ‘placements’ are a key part of becoming an occupational therapist in Australia. Placements give students the chance to learn real‐world skills under the guidance of qualified practitioners. As the number of students grows, it has become harder for universities to find enough suitable placement opportunities. One possible solution is to offer placements in research settings, where students are supervised by allied health practitioners working in research roles. This study explored what occupational therapy and physiotherapy students, practitioners, and university educators think about placements in research settings. Thirty people were interviewed, sharing their experiences and views. Ideas shared in the interviews were sorted into seven main groups: research confidence, professional responsibility, sparking interest, missed opportunity, accreditation requirements, fear of missing out on client contact, and risks to the research quality. Most participants felt that these placements could help students build confidence with using research, learn important skills, and become more interested in research as part of their future careers. However, some participants were unsure whether all research settings would offer enough opportunities for students to develop and demonstrate the necessary skills of a graduate occupational therapist or physiotherapist. Some participants described positive experiences with placements in research settings, whereas others had neither undertaken nor previously considered such placements. Overall, the study found that placements in research settings could help students better understand how research is created and used in their future work roles. For these placements to work well, universities, practitioners, and students will need to work together to design and test potential models.

The requirement for alternative wastewater treatment methods continues to increase as current systems are overwhelmed, leading to accumulation of both microbial and chemical pollutants. The purpose of this study was to evaluate and compare the potential of two distinct PAWs, The bubble spark discharge (BSD) and dielectric barrier discharge diffuser (DBDD), for both microbial inactivation and decolourisation of model organic contaminants in wastewater. The potential mechanisms associated with each PAW was explored using ROS and RNS quantification and chemical scavenger assays. Two direct plasma-in-liquid systems generating PAW in situ via microbubble discharge were evaluated: BSD and DBDD, tested for antimicrobial activity against relevant potential wastewater pathogens including E. coli and S. enterica. Their ability to degrade several water-soluble dyes (crystal violet, methylene blue and Congo red) as relevant surrogates for environmental contaminants of industrial origin, was also assessed. The DBDD achieved the most rapid inactivation of all tested planktonic bacteria within 90 s, while the BSD took up to 5 min. The bactericidal activity of the DBDD was likely due to a greater production of short-lived species such as O₂⁻ and ¹O₂, which specific scavenger assays (L-histidine and Tiron) confirmed were essential for the antimicrobial activity, while the longer-lived H2O2 contributed significantly to the antibacterial activity of the BSD system. These findings suggest that PAW could be used as a rapid, on-demand advanced oxidation process for the tertiary stage of wastewater treatment, with potential to reduce reliance on conventional UV or chlorine disinfection while targeting both chemical contaminants and microbial bioburdens.

Microbial populations strongly shape their environment, which can re-route adaptation toward organism-generated fitness optima. However, the conditions that promote these eco-evolutionary feedbacks are unclear. Here, we used experimental evolution to test whether high population density, by strengthening niche construction, drives eco-evolutionary feedbacks in the bacterial pathogen Pseudomonas aeruginosa MPAO1. We then tested for adaptation to organism-modified environments by measuring the relative performance of ancestral and endpoint populations in filtrate generated by each evolutionary line sampled across generations. Contrary to expectations, we found that endpoint populations had higher performance than the ancestral strain in filtrate across nearly all evolutionary lines regardless of population density. This was caused by the emergence of hyperactive filamentous bacterio(phage) mutants during experimental passaging that inhibited the ancestral strain but not endpoint populations in modified media. Hyperactive phages emerged from one of two avirulent prophages in MPAO1's genome (Pf4 or Pf6). Hyperactive phages drove the evolution of phage resistance in bacterial populations via mutations in the type IV pilus (TIVP), the phage's binding receptor. In a follow-up experiment, we showed that these TIVP mutations pleiotropically reduced motility and decreased susceptibility to a TIVP-targeting virulent phage, both of which are important traits for P. aeruginosa infection and treatment. Overall, this work suggests that filamentous phage evolution can drive of eco-evolutionary feedbacks in bacterial populations, causing phenotypic and genetic changes that would not be anticipated from adaptation to the extrinsic environment alone.

In this work, a high-performance, room-temperature-operated acetone gas sensor is developed based on cladding-modified optical fiber functionalized with hierarchical flower-like ZnO@Ag2O nanostructures. Unlike conventional metal-oxide gas sensors operating at elevated temperatures, the formation of a p-n heterojunction between p-type Ag2O and n-type ZnO facilitates efficient charge separation and significantly lowers the activation energy for acetone oxidation, enabling enhanced sensing at ambient conditions. The structural and morphological properties were characterized by X-ray diffraction, FESEM, XPS, and FTIR. The sensing performance was achieved by coating the modified fiber cladding with ZnO@Ag2O, where evanescent-field interaction and adsorption-induced optical property changes govern the sensing mechanism, as validated by COMSOL Multiphysics simulations. The flower-like morphology provides a larger surface area and abundant active sites, resulting in superior sensing performance compared to pristine ZnO nps. The performance parameters of the developed sensor include a sensitivity of 11.37/ppm, a limit of detection of 0.85 ppm, and response and recovery times of 14 s and 60 s, respectively, compared to pristine ZnO nps. Additionally, the sensor exhibits good selectivity for acetone over different interfering VOC species. Owing to its spark-free operation, low power consumption, and immunity to electromagnetic interference, the proposed sensing platform presents a promising solution for real-time acetone detection in industrial process monitoring and non-invasive biomedical diagnostics.

To identify the specific support needs of Black women navigating infertility care and generate strategies to improve access, patient experience, and outcomes. Mixed-methods observational study SUBJECTS: Black women aged 18-45 years in the US who were currently seeking or had recently sought infertility care EXPOSURE: Online survey and semi-structured interviews MAIN OUTCOME MEASURE: Quantitative data on demographics and fertility care experiences; qualitative data on perceived support needs and recommended solutions RESULTS: 176 women responded to the online survey; of these, 41 women provided consent to participate in semi-structured interviews with the study team. Most participants (74.3%) were 35-45 years of age, married or partnered, held an advanced degree, worked full-time, and had insurance that covered some or all fertility services. 25.5% of participants reported feeling under-supported by friends, family, doctors, or others during their infertility journey, with 31.3% identifying this lack of support as a barrier to initiating treatment. Participants described feelings of loneliness and isolation, with few affirming spaces or communities to find resources and connect with other Black women with infertility. They also shared examples of racism, discrimination, and a lack of compassionate care that led to dismissal of health concerns and delays in referral to reproductive endocrinologists that complicated their infertility journeys. Study participants provided several suggestions for clinics and providers to improve the support of Black women seeking infertility care, from enhancing patient-centered care to increasing access to Black reproductive medicine and mental health providers. Understanding the specific support needs of Black women seeking infertility care will inform patient-centered, compassionate, and culturally responsive care that improves the patient's experience and outcomes.

Current guidelines recommend anifrolumab and belimumab as comparably viable immunosuppressive therapies for active systemic lupus erythematosus (SLE), yet comparative evidence remains limited. Patients with SLE have increased cardiovascular disease (CVD) risk, with dysregulated type I interferon (IFN-I) signaling implicated in disease pathogenesis. We evaluated whether anifrolumab, an IFN-I receptor antagonist, or belimumab confer differing CVD risks to inform treatment selection and patient counseling. We conducted an emulated target trial using electronic health record data from 67 healthcare organizations in the TriNetX network (2020-2025). Adults with SLE initiating anifrolumab or belimumab without prior cardiovascular disease were included. Propensity score matching balanced demographics, comorbidities, laboratory data, and medication use. Outcomes included 3-year risks of myocardial infarction (MI), heart failure (HF), ischemic stroke, and major adverse cardiovascular events (MACE). Cox regression estimated hazard ratios (HR) and 95% confidence intervals. Before matching, 1,091 patients received anifrolumab and 7,492 received belimumab (mean ages 45.6 and 43.7 years, respectively). After matching, the cohort included 1,084 pairs with mean ages of 45.6 and 46.0 years, respectively. Compared with belimumab, anifrolumab treatment was associated with lower risks of MI (HR 0.63; 95% CI 0.40-0.91), HF (0.55; 0.39-0.75), ischemic stroke (0.50; 0.26-0.94), and MACE (0.65; 0.37-0.89). Anifrolumab treatment was associated with lower CVD risk compared with belimumab in patients with SLE, supporting its consideration as a safe therapeutic option, particularly for populations with increased CVD risk. Prospective studies are needed to firmly establish causality.

Cancer-related posttraumatic stress disorder (PTSD) is prevalent among hematopoietic cell transplantation (HCT) survivors, yet access to evidence-based care is limited. This study evaluated adaptive, stepped-care treatment sequences for PTSD symptoms using a Sequential Multiple Assignment Randomized Trial (SMART), comparing digital and therapist-delivered interventions. HCT survivors (N&#xa0;=&#xa0;477), 1-5&#xa0;years post-transplant, with probable or subthreshold PTSD, were randomized to the Cancer Distress Coach (CaDC) app or Usual Care. At Week 4, non-responders (i.e., < 5-point PCL-5 reduction) were re-randomized to CaDC&#xa0;+&#xa0;Coaching or therapist-delivered cognitive behavioral therapy for PTSD (CBT-PTSD). PTSD symptoms (primary outcome), depression, and anxiety were assessed at baseline, Week 4, Month 3 (primary endpoint), and Month 6. Both initial treatment groups demonstrated symptom reductions at Week 4 with no significant between-group differences; approximately 60% met early response criteria. By Month 3, outcomes reflected treatment escalation rather than direct comparison of initial interventions. Regimen-level analyses demonstrated differences across adaptive sequences for PTSD at Months 3 and 6, and for depression and anxiety at Month 3 (global p-values &#x2264; 0.018). Regimens escalating to CBT-PTSD were associated with greater and more sustained reductions than those escalating to CaDC&#xa0;+&#xa0;Coaching. The sequence initiating with CaDC and escalating to CBT-PTSD produced the largest effects. Although a self-guided digital intervention did not outperform Usual Care initially, adaptive stepped-care strategies that triage early responders and escalate non-responders to therapist-delivered CBT-PTSD were associated with the greatest reductions in symptoms. Digital tools may function as entry points within stepped-care models to allocate higher-intensity psychotherapy. ClinicalTrials.gov, NCT04058795, registered 8/16/2019.

TMEM63B, a mechanosensitive ion channel (MSC), is associated with severe neurodevelopmental disorders, including severe early-onset developmental and epileptic encephalopathy. Structure-function studies have shown that TMEM63B pathogenic variants, including V44M in transmembrane helix 0 (TM0) and T481N in TM4, cluster near the hydrophobic neck region of the ion permeation pathway, a region critical for gating and permeation. Notably, V44M and T481N convert TMEM63B into constitutive phospholipid scramblases without obvious effects on their MSC activity, revealing an unexpected channel-to-scramblase switch in these variants. To further define the mechanistic basis of this phenomenon, here we characterized I475del, a TM4 deletion variant near V44M and T481N. Unlike V44M and T481N, the I475del channel exhibited basal leak currents, enhanced mechanically activated currents, and elevated mechanosensitivity, altogether supporting its classification as a bona fide gain-of-function MSC variant. Like V44M and T481N, I475del also enabled constitutive phospholipid scramblase activity. However, unlike these variants, I475del uniquely displayed further potentiation of scramblase activity under hypotonic osmotic stress. In addition, mutating the key residues that control gating conformational changes abolished gain-of-function ion and lipid transport through I475del. Together, our results support a stratified molecular model of TMEM63B channelopathies in which the pathogenic variants progressively destabilize the hydrophobic gate, permitting lipid permeation at the resting state followed by force-induced ion and lipid cotransport. These findings advance the mechanistic understanding of TMEM63B function and TMEM63B-associated disease and provide a framework for developing therapeutic strategies targeting variant-specific pathologies.