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At least 199 records · Page 11

Characterization of xenobiotic metabolizing enzymes of a reconstructed human epidermal model from adult hair follicles

In this study, a comprehensive characterization of xenobiotic metabolizing enzymes (XMEs) based on gene expression and enzyme functionality was made in a reconstructed skin epidermal model derived from the outer root sheath (ORS) of hair follicles (ORS-RHE). The ORS-RHE model XME gene profile was consistent with native human skin. Cytochromes P450 (CYPs) consistently reported to be detected in native human skin were also present at the gene level in the ORS-RHE model. The highest Phase I XME gene expression levels were observed for alcohol/aldehyde dehydrogenases and (carboxyl) esterases. The model was responsive to the CYP inducers, 3-methylcholanthrene (3-MC) and β-naphthoflavone (βNF) after topical and systemic applications, evident at the gene and enzyme activity level. Phase II XME levels were generally higher than those of Phase I XMEs, the highest levels were GSTs and transferases, including NAT1. The presence of functional CYPs, UGTs and SULTs was confirmed by incubating the models with 7-ethoxycoumarin, testosterone, benzo(a)pyrene and 3-MC, all of which were rapidly metabolized within 24 h after topical application. The extent of metabolism was dependent on saturable and non-saturable metabolism by the XMEs and on the residence time within the model. In conclusion, the ORS-RHE model expresses a number of Phase I and II XMEs, some of which may be induced by AhR ligands. Functional XME activities were also demonstrated using systemic or topical application routes, supporting their use in cutaneous metabolism studies. Such a reproducible model will be of interest when evaluating the cutaneous metabolism and potential toxicity of innovative dermo-cosmetic ingredients. - Highlights: • Phase I and II xenobiotic metabolizing enzymes are expressed in ORS-RHE model derived from adult hair follicles. • Xenobiotic metabolizing enzymes are functional in ORS-RHE following either systemic or topical application. • Xenobiotic metabolizing enzymes are inducible in ORS-RHE. • ORS-RHE is a suitable model for studying skin metabolism. • ORS-RHE is a convenient and reliable tool for the evaluation of xenobiotics.

60 APPLIED LIFE SCIENCES↗

Adult dental epithelial stem cell-derived organoids deposit hydroxylapatite biomineral

Ameloblasts are specialized cells derived from the dental epithelium that produce enamel, a hierarchically structured tissue comprised of highly elongated hydroxylapatite (OHAp) crystallites. The unique function of the epithelial cells synthesizing crystallites and assembling them in a mechanically robust structure is not fully elucidated yet, partly due to limitations with in vitro experimental models. Herein, we demonstrate the ability to generate mineralizing dental epithelial organoids (DEOs) from adult dental epithelial stem cells (aDESCs) isolated from mouse incisor tissues. DEOs expressed ameloblast markers, could be maintained for more than five months (11 passages) in vitro in media containing modulators of Wnt, Egf, Bmp, Fgf and Notch signaling pathways, and were amenable to cryostorage. When transplanted underneath murine kidney capsules, organoids produced OHAp crystallites similar in composition, size, and shape to mineralized dental tissues, including some enamel-like elongated crystals. DEOs are thus a powerful in vitro model to study mineralization process by dental epithelium, which can pave the way to understanding amelogenesis and developing regenerative therapy of enamel.

59 BASIC BIOLOGICAL SCIENCES↗

Patient-based estimation of organ dose for a population of 58 adult patients across 13 protocol categories

Purpose: This study aimed to provide a comprehensive patient-specific organ dose estimation across a multiplicity of computed tomography (CT) examination protocols. Methods: A validated Monte Carlo program was employed to model a common CT system (LightSpeed VCT, GE Healthcare). The organ and effective doses were estimated from 13 commonly used body and neurological CT examination. The dose estimation was performed on 58 adult computational extended cardiac-torso phantoms (35 male, 23 female, mean age 51.5 years, mean weight 80.2 kg). The organ dose normalized by CTDI{sub vol} (h factor) and effective dose normalized by the dose length product (DLP) (k factor) were calculated from the results. A mathematical model was derived for the correlation between the h and k factors with the patient size across the protocols. Based on this mathematical model, a dose estimation iPhone operating system application was designed and developed to be used as a tool to estimate dose to the patients for a variety of routinely used CT examinations. Results: The organ dose results across all the protocols showed an exponential decrease with patient body size. The correlation was generally strong for the organs which were fully or partially located inside the scan coverage (Pearson sample correlation coefficient (r) of 0.49). The correlation was weaker for organs outside the scan coverage for which distance between the organ and the irradiation area was a stronger predictor of dose to the organ. For body protocols, the effective dose before and after normalization by DLP decreased exponentially with increasing patient's body diameter (r > 0.85). The exponential relationship between effective dose and patient's body diameter was significantly weaker for neurological protocols (r < 0.41), where the trunk length was a slightly stronger predictor of effective dose (0.15 < r < 0.46). Conclusions: While the most accurate estimation of a patient dose requires specific modeling of the patient anatomy, a first order approximation of organ and effective doses from routine CT scan protocols can be reasonably estimated using size specific factors. Estimation accuracy is generally poor for organ outside the scan range and for neurological protocols. The dose calculator designed in this study can be used to conveniently estimate and report the dose values for a patient across a multiplicity of CT scan protocols.

60 APPLIED LIFE SCIENCES↗

Distinct effects of beta-amyloid and tau on cortical thickness in cognitively healthy older adults

Published reports of associations between β-amyloid (Aβ) and cortical integrity conflict. Tau biomarkers may help elucidate the complex relationship between pathology and neurodegeneration in aging. We measured cortical thickness using magnetic resonance imaging, Aβ using Pittsburgh compound B positron emission tomography (PiB-PET), and tau using flortaucipir (FTP)-PET in 125 cognitively normal older adults. We examined relationships among PET measures, cortical thickness, and cognition. Cortical thickness was reduced in PiB+/FTP+ participants compared to the PiB+/FTP– and PiB–/FTP– groups. Continuous PiB associations with cortical thickness were weak but positive in FTP– participants and negative in FTP+. FTP strongly negatively predicted thickness regardless of PiB status. FTP was associated with memory and cortical thickness, and mediated the association of PiB with memory. Past findings linking Aβ and cortical thickness are likely weak due to opposing effects of Aβ on cortical thickness relative to tau burden. Tau, in contrast to Aβ, is strongly related to cortical thickness and memory.

60 APPLIED LIFE SCIENCES↗

Exploring young adult texts within the Historically Responsive Literacy Framework with preservice teachers

Abstract While culturally responsive texts have become more common in teacher education, too often, preservice teachers (PTs) are not asked to examine how to use these books pedagogically. To address this issue, in a young adult (YA) literature course, the Framework for Culturally and Historically Responsive Literacy (HRL) (Muhammad, 2000) Cultivating genius: An equity framework for culturally and historically responsive literac y, 2020; Scholastic) was used in conjunction with representative and inclusive YA trade books. Data analysis was conducted on PT's course work, including HRL unit plans, to determine whether PTs were able to implement Muhammad's (2020) framework using YA texts. The findings of this study show that PTs' understanding of the HRL tenets was at varying levels. While there were unit plans with learning goals that matched Muhammad's purpose and definition for each tenet and YA connections for every tenet, PTs showed a better understanding of the tenets of identity and intellect than skills and Criticality. Implications of these findings including exposing PTs to learning frameworks “written by people of color and designed for children of color” (Muhammad, 2020, p. 11) to create instruction that meets their future students' needs and does not just skim the surface of culturally responsive pedagogies.

Pule, Heather↗

Xanthohumol Microbiome and Signature in Healthy Adults (the XMaS Trial): Safety and Tolerability Results of a Phase I Triple-Masked, Placebo-Controlled Clinical Trial

Scope Xanthohumol, a prenylflavonoid from hops, has been extensively studied preclinically but has undergone limited research in human subjects. A triple-masked, placebo-controlled phase I clinical trial was conducted to examine the safety and tolerability of xanthohumol. Methods and results Thirty healthy volunteers were randomized to 24?mg/day xanthohumol (99.8% pure) or placebo for eight weeks. Comprehensive metabolic panels, complete blood counts, body weight, vital signs, and health-related quality of life questionnaires were assessed every two weeks. Participants were interviewed for adverse events (AEs) throughout the trial. Thirteen of 14 (93%) and 14 of 16 (88%) participants completed the trial in Group A and B respectively. There were no withdrawals due to AEs. There were no clinically relevant, between-group differences in laboratory biomarkers, body weight, vital signs, or health-related quality of life. There were no severe or FDA-defined serious AEs, but non-serious AEs were documented in both Group A (n=42) and Group B (n=58). Conclusion Over an eight-week period, 24 mg daily xanthohumol was safe and well-tolerated by healthy adults.

Langley, Blake↗

Achieving Productivity to Recover and Restore Columbia River Stream-Type Chinook Salmon Relies on Increasing Smolt-To-Adult Survival

Abstract We analyzed and compared productivity and survival rates of populations of stream-type Chinook Salmon Oncorhynchus tshawytscha from the upper and middle ranges of their distribution in the Columbia River basin. These two groups of populations undergo vastly different exposures during migration through the Federal Columbia River Power System (FCRPS). Declines of the Snake River populations, listed as threatened under the U.S. Endangered Species Act, have been associated with the development and operation of the FCRPS. In contrast, John Day River stream-type Chinook Salmon populations, which were less affected by the FCRPS, have declined to a lesser extent and are not listed. Smolt-to-adult survival rates (SARs) accounted for a majority of the variation in life cycle survival rates of Snake River Chinook Salmon. Productivity declined to 13% and 44% of historical productivity levels for Snake River and John Day River populations, respectively. A synthesis of previous studies contrasting anthropogenic impacts between the two regions supports the conclusion that FCRPS impacts explain the large difference in population productivity. Our results suggest that SARs of 4% would result in an expected productivity of up to 70% of historical levels (a SAR level consistent with regional restoration objectives). The SARs have been shown to be highly influenced by conditions within the FCRPS (e.g., water velocity and passage through dam powerhouses). Marine conditions also influence SARs; however, meaningful management actions are only available to affect conditions within the FCRPS. Given the importance of SARs to overall life cycle productivity, recovery and restoration strategies need to prioritize actions that have potential to substantially increase SARs by addressing the significant impacts of main-stem dams. This study highlights the importance of considering river management options in the face of increasingly variable and warming ocean conditions.

Petrosky, Charles E.↗

Evaluating the frequency and severity of ovarian venous congestion on adult computed tomography

Purpose: While pelvic congestion syndrome and chronic pelvic pain are relatively common in women, no large- or medium-sized studies have been conducted to our knowledge to evaluate the frequency and severity of ovarian vein dilatation (OVD) on computed tomography (CT). The purpose of our study was therefore to analyze a large number of consecutive abdominal and pelvic CT scans in adult women to determine OVD frequency and severity. Methods: An IRB-approved, single-institution retrospective analysis of 1042 consecutive abdominal and pelvic CT scans in women ages 25–65 was performed. Scans were evaluated for the presence and severity of OVD and association with “nutcracker anatomy.” A gradation scheme was developed based on quartile analysis. Results: 143 of the CT scans had OVD (13.7%). Of the positive scans, 96 were bilateral, 29 were left-side only, 18 were right-side only, and 18 had nutcracker-type compression of the left renal vein (14.4% of scans with left or bilateral OVD). In positive scans, the mean and median left OVD were 7.5 and 7 mm, respectively, and right-side were 7.2 and 7 mm, respectively. Based on quartile analysis, OVD grading was mild (< 6 mm), moderate (6–8 mm), or severe (> 8 mm), with moderate including the middle 50% of patients. Conclusions: OVD was found on 13.7% of 1042 consecutive female abdominal and pelvic CT scans, with “nutcracker anatomy” present in 14.4% of the scans with left OVD. Moderate dilatation was defined as an OVD of 6–8 mm at the iliac crests.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Diffusion tensor imaging of the kidney in healthy controls and in children and young adults with autosomal recessive polycystic kidney disease

Objective: To compare diffusion tensor imaging (DTI) of the kidneys and its derived parameters in children with autosomal recessive polycystic kidney disease (ARPKD) versus healthy controls. Methods: In a prospective IRB-approved study, we evaluated the use of DTI to compare kidney parenchyma FA values in healthy controls (age-matched children with no history of renal disease) versus patients with ARPKD. A 20-direction DTI with b-values of b = 0 s/mm{sup 2} and b = 400 s/mm{sup 2} was used to acquire data in coronal direction using a fat-suppressed spin-echo echo-planar sequence. Diffusion Toolkit and TrackVis were used for analysis and segmentation. TrackVis was used to draw regions of interest (ROIs) covering the entire volume of the renal parenchyma, excluding the collecting system. Fibers were reconstructed using a deterministic fiber tracking algorithm. The FA values based on the ROI data, mean length, and volume of the tracks based on the fiber tracking data were recorded. Results: Eight healthy controls (mean age = 12.9 years ± 4.0; 1/8 males) and six ARPKD participants (mean age = 13.8 years ± 8.5; 5/6 males) were included in the study. Compared to healthy controls, patients with ARPKD had significantly lower FA values (0.33 ± 0.03 vs. 0.25 ± 0.02, p = 0.002) and mean track length (16.73 ± 3.43 vs. 11.61 ± 1.29 mm, p = 0.005). Conclusion: DTI of the kidneys shows significantly lower FA values and mean track length in children and young adults with ARPKD compared to normal subjects. DTI of the kidney offers a novel approach for characterizing renal disease based on changes in diffusion anisotropy and kidney structure.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

MicroRNA-3662 expression correlates with antiviral drug resistance in adult T-cell leukemia/lymphoma cells

Highlights: • IRF-4 and c-Rel cooperate in antiviral drug resistance of ATLL. • Expression of miR-3662 was regulated by IRF4 and to a lesser extent by c-Rel. • Expression of miR-3662 was correlated with antiviral drug resistance in ATLL cell lines. Interferon regulatory factor (IRF) 4 and the proto-oncogene c-Rel cooperate in growth and antiviral drug resistance of adult T-cell leukemia/lymphoma (ATLL). To elucidate the target of IRF4 and c-Rel in ATLL, we determined the simultaneous binding sites of IRF4 and c-Rel using ChIP-seq technology. Nine genes were identified within 2 kb of binding sites, including MIR3662. Expression of miR-3662 was regulated by IRF4, and to a lesser extent by c-Rel. Cell proliferation was inhibited by knockdown of miR-3662 and expression of miR-3662 was correlated with antiviral drug resistance in ATLL cell lines. Thus, miR-3662 represents a target for therapies against ATLL.

60 APPLIED LIFE SCIENCES↗

Hippocampus and basal forebrain volumes modulate effects of anticholinergic treatment on delayed recall in healthy older adults

Abstract Introduction Volumes of hippocampus and cholinergic basal forebrain are associated with delayed recall performance and may modulate the effect of a muscarinic receptor antagonist on delayed recall in healthy volunteers. Methods We studied 15 older adults before and after the oral administration of a single dose of 1 or 2 mg of the preferential M1 muscarinic receptor antagonist trihexyphenidyl (Artane™) or placebo in a double‐blind randomized cross‐over design. Hippocampus and basal forebrain volumes were measured using magnetic resonance imaging. Results We found a significant interaction between treatment and hippocampus volume and a trend level effect between treatment and anterior basal forebrain volume on task performance, with an attenuation of the association between volume size and performance with trihexyphenidyl. Discussion These findings suggest a reduction of delayed recall performance with increasing doses of the muscarinic antagonist that is related to an uncoupling of the association of task performance with cholinergic basal forebrain and hippocampus volumes.

Teipel, Stefan J.↗

Associations between cadmium levels in blood and urine, blood pressure and hypertension among Canadian adults

Background: Cadmium has been inconsistently related to blood pressure and hypertension. The present study seeks to clarify the relationship between cadmium levels found in blood and urine, blood pressure and hypertension in a large sample of adults. Methods: The study sample included participants ages 20 through 79 from multiple cycles of the Canadian Health Measures Survey (2007 through 2013) with measured blood cadmium (n=10,099) and urinary cadmium (n=6988). Linear regression models examined the association between natural logarithm transformed cadmium levels and blood pressure (separate models for systolic and diastolic blood pressure) after controlling for known covariates. Logistic regression models were used to examine the association between cadmium and hypertension. Models were run separately by sex, smoking status, and body mass index category. Results: Men had higher mean systolic (114.8 vs. 110.8 mmHg, p<0.01) and diastolic (74.0 vs. 69.6 mmHg, p<0.01) blood pressure compared to women. Although, geometric mean blood (0.46 vs. 0.38 µg/L, p<0.01) and creatinine-adjusted standardized urinary cadmium levels (0.48 vs. 0.38 µg/L, p<0.01) were higher among those with hypertension, these differences were no longer significant after adjustment for age, sex and smoking status. In overall regression models, increases in blood cadmium were associated with increased systolic (0.70 mmHg, 95% confidence interval [CI]=0.25–1.16, p<0.01) and diastolic blood pressure (0.74 mmHg, 95% CI=0.30–1.19, p<0.01). The associations between urinary cadmium, blood pressure and hypertension were not significant in overall models. Model stratification revealed significant and negative associations between urinary cadmium and hypertension among current smokers (OR=0.61, 95% CI=0.44–0.85, p<0.01), particularly female current smokers (OR=0.52, 95% CI=0.32–0.85, p=0.01). Conclusion: This study provides evidence of a significant association between cadmium levels, blood pressure and hypertension. However, the significance and direction of this association differs by sex, smoking status, and body mass index category. - Highlights: • Blood and urinary cadmium levels higher among those with hypertension. • Evidence of association between cadmium levels, blood pressure and hypertension. • Significance and direction of association differs by sex, smoking status, and BMI. • Higher urinary cadmium levels lower hypertension risk for current (female) smokers.

54 ENVIRONMENTAL SCIENCES↗

Irradiation of rainbow trout at early life stages results in a proteomic legacy in adult gills. Part B; the effect of a second radiation dose, after one year, on the proteomic responses in the irradiated and non-irradiated bystander fish

Highlights: • The effects of a 2nd radiation dose at one year were investigated. • The bystander effect proteomic responses in non-irradiated fish were investigated. • The effects of a 2nd radiation dose differed to those of early life irradiation only. • Proteomic responses of irradiated fish indicated tumorigenesis or cancer progression. • Bystander effect proteomic responses were tumorigenic, detrimental or uncertain. This study extends the investigation of the legacy effects of exposure to a single radiation dose at one of four early life stages, in adult rainbow trout (Part A), by examining the effects of a second identical dose after one year; i.e. egg 48 h after fertilisation (48 h egg) + 1 year, eyed egg + 1 year, yolk sac larvae (YSL) + 1 year and first feeder + 1 year. This included the induction of a bystander effect in non-irradiated trout which had swam with the irradiated fish. The second radiation dose negated any beneficial proteomic responses following early life stage irradiation only, particularly irradiation of 48 h eggs and eyed eggs (Part A). Instead the responses after early life stage + 1 year irradiation are consistently associated with tumorigenesis, cancer progression, or are otherwise damaging: upregulation of alpha-globin 1 (YSL + 1 year and first feeders + 1 year) and downregulation of histone H1, type II keratin, malate dehydrogenase 2–2, Na/K ATPase alpha subunit isoform 1b, nucleoside diphosphate kinase (48 h egg + 1 year), electron transfer flavoprotein subunit alpha (eyed egg + 1 year), 60 S ribosomal protein L30 (YSL + 1 year) and haemoglobin subunit beta-4 (first feeder + 1 year). Most significantly the second radiation dose also negated the overwhelmingly beneficial bystander effect proteomic responses induced by trout irradiated at an early life stage only (Part A). Instead the bystander effect proteomic changes induced by trout irradiated at an early life stage and again at 1 year have been associated with uncertain, with respect to tumorigenesis, or detrimental effects; upregulation of alpha-globin 1 (YSL + 1 year and first feeder + 1 year) and downregulation of malate dehydrogenase 2–2, nucleoside diphosphate kinase (48 h egg + 1 year), transferrin precursor (eyed egg + 1 year), 60 S ribosomal protein L30 (YSL + 1 year) and serine / threonine-protein phosphatase 2 A 65 kDa (first feeder + 1 year). This difference between the bystander effect induced proteomic changes following early life stage irradiation only and early life stage + 1 year irradiation may indicate a fundamental change in the non-targeted effects of radiation following multiple exposure to radiation.

54 ENVIRONMENTAL SCIENCES↗

Pathways linking residential noise and air pollution to mental ill-health in young adults

Highlights: • A model with multiple pathways was tested. • Daytime noise was related to poor mental health. • Air pollution had only an indirect effect. • Key mediators: annoyance and neighborhood restorative quality. Recent years have seen growing, but still tentative, evidence of the potential associations of environmental noise and air pollution with mental disorders. In the present study, we aimed to examine the associations between residential noise and air pollution exposures and general mental health in young adults with a focus on underlying processes.

54 ENVIRONMENTAL SCIENCES↗

Short-term effects of particulate matter in metro cabin on heart rate variability in young healthy adults: Impacts of particle size and source

Highlights: • Exposure to metro PM was associated with decreased HRV in young healthy adults. • The strength and lag time for effects of PM on HRV varied by particle size. • Greater decreases in HRV suggested that females were more susceptible to the effects of PM exposure. • Ambient PM from combustion source (indicated by black carbon) has adverse health effects on passengers in cabin. Metro system has become popular in urban areas. However, short-term effects of size-fractionated particulate matter (PM) on cardiac autonomic function in metro system remain unexplored.

54 ENVIRONMENTAL SCIENCES↗

Young Adult Populations Face Yet Another Barrier to Care With Insurers: Limited Access to Proton Therapy

Young patients, including pediatric, adolescent, and young adult (YA) patients, are most likely to benefit from the reduced integral dose of proton beam radiation therapy (PBT) resulting in fewer late toxicities and secondary malignancies. This study sought to examine insurance approval and appeal outcomes for PBT among YA patients compared with pediatric patients at a large-volume proton therapy center.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

APOE effect on Alzheimer's disease biomarkers in older adults with significant memory concern

This study assessed apolipoprotein E (APOE) ε4 carrier status effects on Alzheimer's disease imaging and cerebrospinal fluid (CSF) biomarkers in cognitively normal older adults with significant memory concerns (SMC). Cognitively normal, SMC, and early mild cognitive impairment participants from Alzheimer's Disease Neuroimaging Initiative were divided by APOE ε4 carrier status. Diagnostic and APOE effects were evaluated with emphasis on SMC. Additional analyses in SMC evaluated the effect of the interaction between APOE and [ 18 F]Florbetapir amyloid positivity on CSF biomarkers. SMC ε4+ showed greater amyloid deposition than SMC ε4-, but no hypometabolism or medial temporal lobe (MTL) atrophy. SMC ε4+ showed lower amyloid beta 1-42 and higher tau/p-tau than ε4-, which was most abnormal in APOE ε4+ and cerebral amyloid positive SMC. Lastly, SMC APOE ε4+ show abnormal changes in amyloid and tau biomarkers, but no hypometabolism or MTL neurodegeneration, reflecting the at-risk nature of the SMC group and the importance of APOE in mediating this risk.

60 APPLIED LIFE SCIENCES↗

Heterogeneity of adult masseter muscle satellite cells with cardiomyocyte differentiation potential

Highlights: • Sca1{sup +} MMSCs with cardiogenic signature originate from mesodermal progenitors. • Sca1{sup -} MMSCs maintain skeletal myogenic capacity. • Sca1{sup +} MMSCs can be stably converted into CMs using growth factors. Although resident cardiac stem cells have been reported, regeneration of functional cardiomyocytes (CMs) remains a challenge. The present study identifies an alternative progenitor source for CM regeneration without the need for genetic manipulation or invasive heart biopsy procedures. Unlike limb skeletal muscles, masseter muscles (MM) in the mouse head are developed from Nkx2–5 mesodermal progenitors. Adult masseter muscle satellite cells (MMSCs) display heterogeneity in developmental origin and cell phenotypes. The heterogeneous MMSCs that can be characterized by cell sorting based on stem cell antigen-1 (Sca1) show different lineage potential. While cardiogenic potential is preserved in Sca1{sup +} MMSCs as shown by expression of cardiac progenitor genes (including Nkx2–5), skeletal myogenic capacity is maintained in Sca1{sup -} MMSCs with Pax7 expression. Sca1{sup +} MMSC-derived beating cells express cardiac genes and exhibit CM-like morphology. Electrophysiological properties of MMSC-derived CMs are demonstrated by calcium transients and action potentials. These findings show that MMSCs could serve as a novel cell source for cardiomyocyte replacement.

60 APPLIED LIFE SCIENCES↗