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Changes in metabolic energy measures for daily living activities and exercise in men and women following arduous activity in Antarctica

PLoS ONE John Hattersley, C. Doug Thake, Chris Imray et al. Oct 31, 2025 DOI: 10.1371/journal.pone.0335735

This study reports pre- to post-expedition (pre|post) changes in energy expenditure and substrate utilisation during daily living activities (DLAs including rest, sleep, modest exercise, sedentary work and leisure) and maximum aerobic power ( V ˙ O2max ) for participants in the Inspire-22 expedition (6 men, 3 women) who undertook a 47 day unassisted Antarctic traverse from the Ronne Ice Shelf to the South Pole. DLA measurements were carried out during a 36 hour study in a whole-body calorimeter whilst measurements of maximum oxygen uptake ( V ˙ O2max ), capillary glucose and lactate during incremental stepping exercise to volitional exhaustion were carried out under normobaric normoxic and hypoxic (14% O2) conditions in an environmental chamber. Non-exercise measures were normalised to non-fat tissue weight; exercise measures, including those in the DLAs, to body weight. Statistical analysis used the Aligned Rank Transform (ART) non-parametric ANOVA technique with covariants pre|post expedition, sex and hypoxia|normoxia as appropriate. There were no systematic differences between pre- and post-expedition energy expenditure but significant differences between men and women for the majority of the DLAs (p < 0.05). There was increased carbohydrate utilisation post-expedition for sleep and the two lower intensity exercise levels (p < 0.05) but not during rest or the highest intensity exercise (p > 0.05); a sex-independent subset of 4 showing much higher utilisation. Women had a lower protein utilisation than men during the DLA exercise activities (p < 0.05). V ˙ O2max was lower in hypoxia than normoxia (p < 0.001) and reduced glucose and lactate between pre- and post-expedition measures. There was also a significant interaction between sex and pre|post measurements for V ˙ O2max and lactate suggesting that adaptation to the environment and high workloads was different between men and women; a suggestion supported by the difference in fat-free tissue measured pre- and post-expedition, but neither sex showed major differences between the pre- and post-expedition measurements.

Analysis of galloping response in ice-coated transmission conductors under wind loads

PLoS ONE Shuang Wu, Haiqing Liu, Yunlong Wang et al. Oct 31, 2025 DOI: 10.1371/journal.pone.0335594

Conductor galloping is a low-frequency, large-amplitude vibration phenomenon induced by the combined action of ice accretion and wind loads, which poses severe threats to power grid safety. For 500 kV transmission lines in Xinjiang, a strain-displacement relationship based on elastic catenary theory was developed, establishing a nonlinear dynamic model for galloping of ice-coated bundled conductors with torsional stiffness. Employing D-shaped, fan-shaped, and crescent-shaped ice-accreted bundle conductors, this work investigates the influence of wake effects and wind attack angles on aerodynamic characteristics at varying spanwise lengths. Subsequently, aerodynamic loads were computed based on the derived aerodynamic coefficients, enabling galloping response analysis of ice-accreted bundle conductors. The results demonstrate that the proposed methodology facilitates efficient analysis of galloping amplitude in ice-accreted transmission conductors, and the three-dimensional numerical model significantly improves the computational accuracy of aerodynamic forces on bundle conductors. The flow field around ice-coated bundled conductors exhibits pronounced periodicity, governed collectively by wake effects, wind attack angle, ice accretion geometry, ice thickness, and wind velocity. Additionally, spacer bars with articulated connections suppress conductor galloping more effectively.

Lacrimispora sanguinis sp. nov., isolated from human blood

PLoS ONE Hui-Jin Yu, Yun Young Cho, Jayoung Paek et al. Oct 31, 2025 DOI: 10.1371/journal.pone.0334875

A rod-shaped, obligate anaerobic, Gram-stain-positive bacterium isolated from the human blood was designated as the strain HJ-01 T . Analysis of the 16S rRNA gene sequence revealed that the strain HJ-01 T belonged to the genus Lacrimispora , and was most closely related to L. celerecrescens strains DSM 105336 and MCM B-936, with both 99.3% similarity. The average nucleotide identity values between the strain and the most closely related type strains ranged from 75.3% to 91.4%, while the values between the strain and the two non-type strains of L. celerecrescens , DSM 105336 and MCM B-936, were 98.8% to 98.9%. The digital DNA-DNA hybridization values between the strain and the most closely related type strains ranged from 19.8% to 44.5%, whereas the values between the strain and L. celerecrescens strains DSM 105336 and MCM B-936 were 89.7% to 91.6%. The phylogenomic analysis revealed that the strain formed a cluster adjacent to L. celerecrescens strains DSM 105336 and MCM B-936. The main fatty acids identified were C 16:0 and C 18:1 cis 11 DMA. The cell wall contained the meso -diaminopimelic acid-based peptidoglycan. The end products of the fermentation were acetic acid and formic acid. The strain HJ-01 T and the related Lacrimispora strains shared similar antibiotic resistance profiles, including high resistance to clindamycin (8–256 µg ml−1), linked to the cfr (C) gene located within a 3,378-bp chromosomal transposed unit. Given the chemotaxonomic, phenotypic, and phylogenetic properties, HJ-01 T (= KCTC 25933 T  = JCM 37550 T ) represent a novel species of the genus Lacrimispora , for which the name Lacrimispora sanguinis sp. nov. is proposed. Additionally, we suggest that L. celerecrescens DSM 105336 and MCM B-936 be transferred to Lacrimispora sanguinis sp. nov.

Drug-induced movement disorder: A disproportionality analysis using the FDA adverse event reporting system (FAERS) from 2004 to 2024

PLoS ONE Jingjing Zou, Chenju Zhan, Yan Feng et al. Oct 31, 2025 DOI: 10.1371/journal.pone.0335449

Background Although many drugs have been associated with drug-induced movement disorders (DIMDs), the associated risks are unclear. This study aimed to identify high-risk drugs for DIMDs through disproportionality analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database and to explore risk factors for DIMDs through sensitivity analysis. Methods Four disproportionality analysis methods were used to assess the risk signals of drugs that may induce DIMDs from the first quarter of 2004 to the fourth quarter of 2024. One-way analyses, LASSO analyses, and logistic regression analyses were performed to explore the risk factors associated with DIMDs. Results There are 138,081 reports related to DIMDs. This study identified 148 suspected drugs. Age under 33 years, male gender, and 62 medications, including METOCLOPRAMIDE, ARIPIPRAZOLE, CARBIDOPA, LEVODOPA, RISPERIDONE, and QUETIAPINE, are all independent risk factors for drug-induced movement disorders. The area under the ROC curve (AUC) reflecting model predictive accuracy was 0.724. Conclusion Our disproportionality analysis and sensitivity analysis of the FAERS database identified drugs potentially associated with DIMDs. These findings can provide valuable information for clinicians to be more cautious when prescribing these drugs and to monitor patients for the development of movement disorders closely. Additionally, the results can help regulatory agencies make informed decisions regarding the safety of drugs.

Non-linear association of sleep duration with osteoarthritis among middle-aged and older adults: Results from a prospective cohort study in China

PLoS ONE Long Long, Qi Wang, Bohao Fang et al. Oct 31, 2025 DOI: 10.1371/journal.pone.0335552

Background The association between nighttime sleep duration and osteoarthritis (OA) remains ambiguous. Chinese older adults exhibit distinct sleep patterns, as well as genetic predispositions and rapidly changing lifestyles, which may have shaped the unique epidemiology of OA. However, most existing evidence is based on Western populations. This study aimed to investigate this association and the potential moderating role of BMI in middle-aged and older Chinese adults. Methods Data of wave 1 (2011) and wave 4 (2018) were obtained from the nationally representative China Health and Retirement Longitudinal Study (CHARLS). Univariate and multivariate logistic regression models were utilized to explore the association of sleep duration and OA with sleeping 7–9 h as reference group. Additionally, to further explore the potential combined effect of sleep and BMI, interaction terms were added into the model. Restricted cubic spline was also used to explore the non-linear correlation between sleep duration and OA. Results Out of 6,825 participants, 1,396 were diagnosed with OA. After multivariable adjustment, the odds ratios (OR) for OA were 1.39 (95% CI 1.20–1.60; P < 0.001) for individuals with sleep duration (<6 h/night) and 1.27 (95% CI 1.20–1.60 P = 0.003) for individuals with sleep duration (6–7 h/night). The association between sleep duration and OA followed a U-shaped pattern, with 7.5 h acting as an inflection point. Significant interactions were found in overweight individuals, with both short (OR = 1.41, P = 0.042) and long (OR = 2.71, P = 0.006) sleep durations increasing OA risk. Conclusions Short sleep duration (<7h) was associated with a higher incidence of OA. A U-shaped association was observed between sleep duration and OA incidence among middle-aged and older Chinese adults. BMI may act as a moderator in this relationship.

Patent quality and trade credit: Based on the perspective of knowledge breadth

PLoS ONE Yihan Li, Man Wang Oct 31, 2025 DOI: 10.1371/journal.pone.0335515

Firms often rely on their own unique knowledge to obtain profits, but the reproducibility of knowledge will weaken economic interests, so firms adopt patents to establish exclusivity to clarify the ownership of profit rights. However, patents are only a form, and what kind of knowledge is contained behind them is the key to whether a firm can obtain and how much economic benefit it can obtain. In order to protect intellectual property rights in an all-round way, firms often hold a lots of patents, forming a patent matrix containing multiple cross-knowledge. The more complex the knowledge connotation of the patent matrix, the more difficult it is to be imitated, and the better the protection benefits of patents, forming high-quality patents. This study selects China’s A-share listed companies from 2006 to 2023 as the sample, utilizes patent acquisition data of listed firms, and measures corporate patent quality from the perspective of knowledge breadth—the wider the knowledge breadth embedded in patents, the higher the patent quality. Based on this framework, this study investigates how patent quality, measured by knowledge breadth, influences firms’ access to trade credit. The findings reveal that improvements in corporate patent quality significantly enhance access to trade credit access, with this effect being more pronounced among non-state-owned enterprises and firms in patent-intensive industries. Further analysis demonstrates that patent quality facilitates trade credit access by strengthening bargaining power and elevating corporate reputation. This research not only clarifies the mechanism that ultimately reinforces the operationalization of innovation-driven development frameworks by enhancing firms’ technological competitiveness and market credibility, but also enriches the channels through which patents influence corporate financing, and provides policy recommendations to advance patent quality development. These findings enable firms to leverage patent assets in reducing transaction costs and financing burdens.

The involvement of microglia and the CXCL16-CXCR6 axis in the recruitment of CD8+ T cells to an amyloidogenic mouse brain

Scientific Reports Marco Zattoni, Sabine Bernegger, Sofia Weinbender et al. Oct 31, 2025 DOI: 10.1038/s41598-025-22137-5

Abstract Alzheimer’s disease (AD) progression has been associated with the presence of brain-resident CD8 + T cells, and recent studies suggest a potential role of the CXCL16-CXCR6 axis in their recruitment to the brain. Here, we examined publicly available single-cell RNA sequencing datasets revealing that in the mouse brain, the receptor Cxcr6 is mainly expressed by CD8 + T cells, while the expression of its ligand Cxcl16 is predominantly observed in microglial cells. We found higher levels of Cxcl16 and Cxcr6 expression in APP/PS1 compared to wild-type mice. Furthermore, in vitro experiments using immortalized and primary murine cells suggested that Cxcl16 expression is driven by Aβ pathology. In contrast to our expectations, no changes in the number of Cxcr6 + CD8 + cells was evident in the brains of microglia-depleted APP/PS1 mice, treated with the CSF1R antagonist PLX5622. This was related to an increased compensatory Cxcl16 expression by depletion-resistant microglia or by other brain-resident myeloid cells. Although we demonstrated a strong association between microglial Cxcl16 and AD pathology, PLX5622-sensitive microglia are dispensable in the recruitment of Cxcr6 + CD8 + T cells to the brain of APP/PS1 mice. Future in vivo analysis will help to dissect the mechanism of CD8 + T cell recruitment to the brain.

A porcine model of Fanconi anemia

PLoS ONE Brandon Hergert, Kristin M. Whitworth, Devorah C. Goldman et al. Oct 31, 2025 DOI: 10.1371/journal.pone.0335854

Although small animal models of Fanconi anemia (FA) are useful, they do not faithfully replicate many of the clinical features seen in FA patients. We reasoned that a porcine model of FA with its similar physiology and a relatively long lifespan would produce a phenotype more similar to human FA. Targeting FANCA in domestic swine resulted in skeletal abnormalities and extreme sensitivity to interstrand DNA cross-linking agents. In addition, FANCA disruption followed by mitomycin C treatment resulted in a > 10-fold increase in chromosomal radials, a finding that is considered diagnostic for human FA. Bone marrow derived, hematopoietic progenitor cells from a FANCA null pig showed a 75% reduction in colony forming activity compared to wild type. Evaluation of steady state hematopoiesis in the peripheral blood revealed the gradual development of red cell macrocytosis and a reduction in circulating neutrophils. Targeting of FANCD2 failed to produce any biallelic animals demonstrating the loss of FANCD2 function is embryonic lethal in pigs. These results indicate that a porcine model of FANCA holds promise for the development of strategies to prevent the development of bone marrow failure and malignancies in patients with FA.

Scenario based assessment of carbon storage and habitat quality under land use change in Shandong Province China

Scientific Reports Kechen Lyu, Zhengjun Li Oct 31, 2025 DOI: 10.1038/s41598-025-25097-y

Correction: “It’s wishy-washy [...] You are getting this diagnosis because we’ve ruled out everything else.” Developmental language disorder (DLD) diagnosis in the Republic of Ireland: A qualitative exploration of the perspectives of parents and clinicians

PLoS ONE Oct 31, 2025 DOI: 10.1371/journal.pone.0335868

Novel strategies for enhancing lap spliced reinforced concrete beam behavior for mitigating failure risk

Scientific Reports Sabry Fayed, Moataz Badawi, Mohamed Ghalla et al. Oct 31, 2025 DOI: 10.1038/s41598-025-15511-w

E-health literacy levels of multiple sclerosis patients in Lebanon

PLoS ONE Maria Rita Lteif, Joumana Kalot, Mahmoud El Jaouni et al. Oct 31, 2025 DOI: 10.1371/journal.pone.0335084

Background Having high levels of e-health literacy has been shown to positively influence health-promoting behaviors by empowering patients with greater self-efficacy and improving their health management. Multiple Sclerosis (MS) in Lebanon presents a unique case for studying e-health literacy due to several socio-economic and healthcare-specific challenges faced by this population. Aim This study aimed to evaluate the e-health literacy levels of MS patients in Lebanon and identify the barriers they face when accessing health-related information online. Methods This study employed a mixed-methods approach, combining an online structured survey with qualitative in-depth interviews. The eHealth Literacy Scale (eHEALS) was incorporated to quantify participants’ e-health literacy levels, selected for its well-established reliability and validity, as well as its availability in both English and Arabic. Additionally, the Lily Model was used to guide various phases of the study, providing a conceptual framework for understanding and interpreting e-health literacy. Results Among participants, 45 (31.5%) had limited eHEALS scores while 98 (68.5%) had sufficient eHEALS scores, indicating an overall sufficient e-health literacy among MS patients. However, qualitative findings revealed previously unidentified challenges, including limited confidence in assessing the credibility of online content, emotional distress triggered by exaggerated MS information online, and high reliance on general search engines and social media platforms. Participants expressed lack of access to trusted disease-specific information and voiced a need for professional guidance and well-established peer support. Conclusion These findings call for targeted health promotion interventions to enhance this population’s e-health literacy levels. It is important to equip MS patients from the point of diagnosis with the necessary skills and self-efficacy to effectively utilize online health resources and enhance their disease management journey. This calls for coordinated efforts from well-established MS patient groups, healthcare providers, academic and private institutions to support and empower this population in navigating the digital health landscape.

Dynamic transcriptomic and metabolomic adaptation mechanisms of Trifolium ambiguum under different durations of cold stress

Scientific Reports Kefan Cao, Sijing Wang, Qian Wu et al. Oct 31, 2025 DOI: 10.1038/s41598-025-22148-2

Symptom profiles in lung cancer survivors: A latent class approach

PLoS ONE Tehreem Hussain, Elisa H. Son, Gwenyth R. Wallen et al. Oct 31, 2025 DOI: 10.1371/journal.pone.0309272

Lung cancer survivors experience multiple concurrent symptoms after cancer treatments. However, the majority of symptom research has focused on assessing and managing individual symptoms. Furthermore, little is known about the risk factors and adverse outcomes of complex symptoms in lung cancer survivors. The purpose of the study was to: (1) identify symptom profiles in lung cancer survivors; (2) determine influencing factors of the symptom profiles; and (3) examine differences in health outcomes among the symptom profiles. A cross-sectional secondary analysis of data from the Measuring Your Health (MY-Health) study was conducted with 526 lung cancer survivors. Symptom profiles were identified using latent profile analysis based on four patient-reported symptoms (pain, fatigue, sleep disturbance, and depression) with custom PROMIS ® short forms. We conducted multinomial logistic regression analysis to determine influencing factors of the symptom profiles and multivariate analysis of variance to examine differences in physical function and social function among the symptom profiles. Four latent class symptom profiles were identified: (1) Within Normal Limits (Class 1), (2) Pain with Fatigue and Sleep Disturbance (Class 2), (3) Depression with Fatigue and Sleep disturbance (Class 3), and (4) All High Symptom Burden (Class 4). Age, income, employment status, and number of comorbidities were the influencing factors of the symptom profiles. There were significant differences in physical function and social function among the symptom profiles. This study found that the influencing factors of the symptom profiles in lung cancer survivors tended to be more sociodemographic in nature, rather than clinical. Researchers and healthcare providers use findings such as these when establishing symptom management strategies for lung cancer survivors by integrating demographic and socioeconomic determinants of health in conjunction with targeted clinical variables.

Design of a compact digital to analog converter with optical Kerr effect

Scientific Reports Fariborz Parandin, Mohammadreza Jomour, Babak Karami Oct 31, 2025 DOI: 10.1038/s41598-025-22110-2

Homogenized and stigmatized: A discourse analysis of Asian sub-ethnic medical school aspirants

PLoS ONE Salman H. Choudhry, Keegan D’Mello, George Kim et al. Oct 31, 2025 DOI: 10.1371/journal.pone.0335860

The study examines the influence of Asian sub-ethnic identity on the experiences of pre-medical students in the United States and Canada, aiming to understand how early interactions with the medical education system shape their pursuit of medicine. The researchers analyzed 132 discussion threads from popular online premedical school forums between June 2018 and 2023. The Asian Critical Theory framework guided the analysis along with cyclical inductive coding. Two major themes emerged: the homogenization of diverse Asian sub-ethnicities and external pressure related to sociocultural values. Terms like “over-represented minorities” contributed to the perception of Asians as a monolithic group, while expressions such as “Asian Parents” highlighted unique familial expectations. Non-Asian users often dismissed these barriers, reinforcing the model minority myth. The study emphasizes the negative consequences of framing Asians as a homogenous group in medical school admissions policies, perpetuating stereotypes, and overlooking the diversity within Asian sub-ethnic communities. The term “overrepresented” is critiqued for its role in homogenizing Asian identities and undermining the complexity of their experiences. These findings highlight the need for greater recognition of the nuanced challenges faced by Asian sub-ethnic medical trainees and the importance of dismantling stereotypes in medical education.

Optical, structural, and gamma shielding characteristics of bismuth-doped lithium borosilicate glass composite

Scientific Reports A. Kh. Helmy, E. Salama, M. A. Azooz et al. Oct 31, 2025 DOI: 10.1038/s41598-025-23089-6

Abstract This study investigates the optical, structural, and gamma radiation shielding properties of bismuth-doped lithium borosilicate glass composites. Glasses containing 0–20 mol% Bi₂O₃ were synthesized and analyzed using XRD, FTIR, density measurements, and UV–Vis spectroscopy. All samples exhibited an amorphous structure. The density increased markedly from 2.31 g/cm³ (0 mol% Bi₂O₃) to 4.59 g/cm³ (20 mol% Bi₂O₃), accompanied by a molar volume expansion from 27.33 to 31.02 cm³/mol. Optical studies revealed a progressive reduction in the band gap energy from 3.44 eV to 2.39 eV, while the Urbach energy increased from 0.216 eV to 0.488 eV, indicating enhanced structural disorder with Bi₂O₃ incorporation. Gamma attenuation analysis showed a significant improvement in shielding efficiency: at 0.662 MeV, the mass attenuation coefficient reached 9.83 × 10⁻² cm²/g with an effective atomic number up to 22.24, compared to only 7.76 × 10⁻² cm²/g for Portland concrete. Moreover, the half-value layer decreased with Bi₂O₃ loading, confirming improved attenuation performance. These results highlight that bismuth-doped lithium borosilicate glasses are promising lead-free materials for medical and nuclear radiation shielding applications.

Enhanced phosphorus elimination from aquatic systems employing modified granular waterworks derived sludge composite materials: Mechanistic evaluation and process optimization

PLoS ONE Liwenze He, Jintao Yan, Lin Wang et al. Oct 31, 2025 DOI: 10.1371/journal.pone.0334439

A novel granular waterworks-derived sludge composite (GT La-WDS) was synthesized via green and low-carbon hydrothermal carbonization combined with a calcination-free granulation method, demonstrating exceptional phosphate adsorption performance and potential as constructed wetland filler. Comprehensive characterization (SEM, XRF, BET, FTIR, XRD) revealed its hierarchical porous morphology, chemical composition, and hydroxyl/ligand-functionalized surfaces. Optimal phosphate adsorption capacity (20.11 mg/g) was achieved at pH 4, with adsorption mechanisms dominated by ligand substitution and formation of inner-sphere complexes, as supported by quasi-second-order kinetic modeling and Freundlich isotherm conformity. Dynamic column tests showed prolonged breakthrough (from 168 h to 432 h) and exhaustion times (from 588 h to 2088 h) with increasing bed heights (10 cm to 30 cm), achieving total adsorption capacities of 9.276 mg/g. Effluent phosphate concentrations remained below 0.5 mg/L (Chinese National Effluent Standard Class 1B) for 588 h, with sustained removal efficiency over 2088 h, indicating remarkable longevity. This sludge-derived composite presents a cost-effective solution for phosphorus sequestration, offering dual benefits of eutrophication mitigation and sustainable sludge valorization, with particular relevance to low-carbon constructed wetland systems.

Effect of varying nano-boron nitride content on foamed concrete containing titanium dioxide nanoparticles

Scientific Reports Md Azree Othuman Mydin, Nadhim Hamah Sor, Ziad N. Taqieddin et al. Oct 31, 2025 DOI: 10.1038/s41598-025-22018-x

One IV HEDGES DNA vector administration encoding hGLA or hGH produces durable hGLA and hGH serum lvels in immunocompetent mice

PLoS ONE Alice Ye, Marissa Mack, Sarah Ursu et al. Oct 31, 2025 DOI: 10.1371/journal.pone.0318977

The great majority of human monogenic, single protein deficiency disease patients, who comprise ~ 0.5% of the population, are incurable. When available, Enzyme Replacement Therapy (ERT) is current state-of-the art therapy for the vast majority of the subset of these diseases caused by enzyme deficiencies. For example, Fabry disease, caused by hemizygous- or heterozygous-pathogenic variants in GLA encoding human-galactocersbrosidase-α (hGLA), is a rare, single protein-deficiency disease. Fabry patients require intravenous-administration of hGLA Enzyme Replacement Therapy (ERT) every two-weeks for-life. ERT costs ~ $300,000 per-year and can cause frequent infusion reactions, which can be life-threatening. The very-high yearly GLA ERT costs, as well as the recurrent, life-threatening hGLA IV infusion-reactions experienced by some patients, can cause them to permanently-discontinue ERT. This can accelerate Fabry-disease progression, leading to premature-death. Therefore, new, more effective-, safe-, durable-, cost-effective, single deficient-protein replacement platforms are urgently-needed to more-effectively treat a wide-spectrum of these rare, monogenic single protein deficiency diseases. Here we demonstrate that one intravenous-administration of our 1 st -generation HEDGES DNA-vector encoding wildtype-hGLA (T 1 / 2 < 20-minutes) produced hGLA serum-protein levels in the normal human 1,000-10,000 pg/ml range for only < 14 days. We then-created our 2 nd -generation HEDGES hGLA DNA-vector. One intravenous-administration of this DNA-vector produced durable (>550 days) serum hGLA serum levels in the 1–10 ng/ml, thus increasing the duration of hGLA serum-protein levels produced by > 38,100 fold versus administering bioreactor-produced, wildtype hGLA-protein. We also showed one intravenous-administration of our 1 st -generation HEDGES DNA-vector encoding the wildtype human growth hormone (hGH) protein, (T 1 / 2 < 20-minutes), produced serum hGH levels in the 1–10 ng/ml for > 330 days, thus increasing the duration of hGLA serum-protein levels by > 22,860 fold versus administering wildtype hGH-protein. Last, one intravenous-administration of our 2 nd -generation HEDGES hGLA DNA-vector produced serum hGLA levels in the normal human 1–10 ng/ml range for > 160 days in GLA knockout-mice, a 2,800-fold increase versus wildtype hGLA-protein. hGLA-ERT produces major therapeutic-responses in GLA knockout-mice. These substantial ERT-responses in GLA knockout-mice have been shown to be accurately-recapitulated in Fabry patients. Thus, Fabry disease appears a promising-target for subsequent phase-1 HEDGES-based human clinical trials.