Objective To explore the association between dynamic indexes of maternal progesterone in early pregnancy and the average level and growth rate of fetal head circumference(HC)in mid-and late pregnancy.Methods This study adopted a retrospective cohort design and included 255 singleton pregnant women in the maternal and infant cohort of The First Affiliated Hospital of Xi'an Jiaotong University from January 2015 to December 2024.The progesterone levels of their early venous blood were detected and divided into two groups of progesterone trajectories,namely,fluctuating type and increasing type,by morphology.The dynamic indicators of progesterone in early pregnancy were constructed:cumulative dynamic deviation index in the first trimester(CDDI-P1T),gestational age at progesterone peak(GA-PP),and maximal relative progesterone decline in the first trimester(MRD-P1T).The average head circumference level and linear growth rate of the fetuses in the middle and late pregnancy were calculated.Generalized linear regression(GLM)was used to analyze the linear association between progesterone dynamic indicators and head circumference development.The key gestational weeks of progesterone affecting fetal head development were explored by linear regression of gestational weeks.Ordinary least squares(OLS)regression and restricted cubic spline(RCS)plots were used to draw the nonlinear association between progesterone dynamic indicators and head circumference.Results Among the 255 pregnant women included,92.5％of the progesterone trajectories in early pregnancy were fluctuating,and 7.5％were increasing.The growth rates of the increasing progesterone trajectory group were higher in the second and third trimesters than in the fluctuating group,but the differences were not statistically significant(all P＞0.05).GLM analysis showed that for every 1 unit increase in CDDI-P1T,the head circumference in the middle and late pregnancy increased significantly by 1.574 cm and 1.193 cm(Z=3.714,2.885,P＜0.01).The delay of GA-PP was negatively correlated with the head circumference in the middle pregnancy(β=-0.190 cm,95％CI:-0.339--0.041,P=0.010)but positively correlated with the head circumference growth rate in the late pregnancy(β=0.022 cm/week,95％CI:0.003-0.041,P=0.025).A 10％decrease in the decline of CDDI-P1T increased the head circumference in the middle pregnancy by 0.200 cm(95％CI:0.016-0.384,P=0.033),and a 100％decrease in the decline increased the head circumference growth rate in the late pregnancy by 0.201 cm/week(95％CI:0.002-0.399,P=0.048).The analysis of the key time window showed that for every 20 nmol/L increase in progesterone during 9.5-13 weeks of pregnancy,the mid-term head circumference increased by 0.035-0.166 cm(Z=2.452-3.517,allP＜0.05),and the late-term head circumference increased by 0.767 cm during 9-13 weeks of pregnancy(Z=2.452-3.517,all P＜0.05).When progesterone increased during 9.5-10.5 weeks of pregnancy,the growth rate of mid-term head circumference increased by 0.013-0.023 cm/week(Z=2.074-2.243,all P＜0.01).When progesterone increased during 8.5-10.5 weeks of pregnancy,the growth rate of late-term head circumference increased by 0.010-0.026 cm/week(Z=2.061-3.137,all P＜0.05).Conclusion Progesterone dynamic index is a new sensitive tool for evaluating fetal head circumference development.There is a stage-specific window period for progesterone regulation.9.5-13 weeks of pregnancy is the critical period for progesterone to affect head circumference growth,and 9.5-10.5 weeks of pregnancy is the core window for regulating the growth rate of head circumference.Therefore,it is necessary to combine progesterone dynamic index and time window for individualized intervention to promote the transformation of prenatal care from pregnancy maintenance to eugenics intervention.

Objective:To observe any effect of combining transcranial magnetic stimulation (rTMS) with aerobic exercise on the cognitive functioning of early stage Parkinson′s disease (PD) patients.Methods:A total of 120 PD patients in the early stage were randomly divided into an observation group and a control group, each of 60. Both groups received conventional drug treatment and moderate-intensity aerobic exercise training, while the observation group was additionally provided with high-frequency rTMS treatment. Before and after 3 months of the treatments, everyone′s cognitive and motor functioning was evaluated using the Montreal Cognitive Assessment Scale (MoCA) and the third part of the Unified Parkinson′s Disease Rating Scale (UPDRS-Ⅲ), respectively. Negative emotions were evaluated using the Hamilton Anxiety Scale (HAMA) and the Hamilton Depression Scale (HAMD). Auditory event-related potentials were also detected, and the latency and amplitude of P300 were analyzed.Results:The average MoCA, UPDRS-Ⅲ, HAMA and HAMD scores, as well as the amplitude and latency of P300 had improved significantly in both groups after the treatment. At that point the observation group′s performance was significantly better than that of the control group in terms of the MoCA′s visuospatial and executive function, attention and delayed recall indicators, and also total score. The observation group′s average HAMA score (10.55±3.11), HAMD score (9.78±4.10), the P300 amplitude [(11.29±2.21)μV] and latency [(384.75±48.26)ms] were also significantly better. The UPDRS-Ⅲ scores were negatively correlated with the visuospatial and executive function scores of the MoCA scale in the observation group before and after treatment, while the average HAMA score was negatively correlated with the attention and delayed recall scores.Conclusions:Supplementing aerobic exercise with rTMS can significantly improve the cognition and motor functioning of early stage PD patients. The combination is more effective than aerobic exercise alone. Such combined therapy is worthy of popularization and clinical application.

Objective:To assess cognitive impairment in children with obstructive sleep-disordered breathing (OSDB) using event-related potentials (ERPs).Methods:This case-control study analyzed data from 143 OSDB children[94 males, 49 females, aged 9.0(7.0-11.0) years] scheduled for adenotonsillectomy at the Department of Otolaryngology-Head and Neck Surgery, Beijing Tsinghua Changgung Hospital, Tsinghua University, between June 2023 and September 2024, along with 17 healthy controls [control group: 10 males, 7 females, aged 10.0 (7.5-12.0) years]. Based on polysomnography results, OSDB children were divided into a mild group [obstructive apnea-hypopnea index (OAHI)≤5 events/hour, 49 males, 29 females, aged 9.0 (7.0-10.0) years] and a moderate-to-severe group [OAHI>5 events/hour, 45 males, 20 females, aged 9.0 (8.0-10.0) years]. All children completed a face perception integration task. The occipital P100 and parietal, central and frontal P300 components of incomplete face stimuli (S1) and complete face stimuli (S2) were recorded. Amplitude and latency differences across groups were analyzed. Intergroup comparisons were performed using ANOVA, while independent samples t-tests were used for pairwise comparisons. Non-normally distributed data were analyzed using the Mann-Whitney U test. Results:(1) P100: Both the mild group [occipital P100 amplitude: O1-S1(12.44±5.96) μV, O2-S1(14.19±6.39) μV, O2-S2(30.34±11.30) μV] and moderate-to-severe group [O1-S1 (12.12±5.58) μV, O2-S1 (14.08±5.48) μV, O2-S2(29.12±10.89) μV] showed significantly higher amplitudes than the control group [O1-S1(8.46±4.74) μV,O2-S1(9.68±3.70) μV,O2-S2(23.09±9.16) μV] ( F=3.501, 4.486, 3.072; all P<0.05). No significant differences were found between the two OSDB subgroups ( P>0.05), suggesting compensatory neuronal hyperactivity maintaining normal perceptual function. The moderate-to-severe group exhibited significantly prolonged P100 latency [O2-S1 (134.52±13.42) ms] compared to controls [O2-S1 (125.18±15.31) ms] ( F=3.156 , P<0.05), while no significant difference was observed between the mild group and either the control or moderate-to-severe groups ( P>0.05), indicating delayed visual processing in severely affected children. (2) P300: The mild group exhibited significantly higher P300 amplitudes in parietal regions [P4-S1(8.22±4.32) μV, P4-S2(17.67±9.42) μV] compared to controls [P4-S1 (4.84±2.89) μV, P4-S2 (13.19±7.23) μV] ( F=7.19, 4.771; both P<0.05), whereas no significant differences were observed between the moderate-to-severe group and either the control or mild groups ( P>0.05), indicating mild group reduced alertness. The latency of P300 in the central region showed an increase in the mild group, although not significantly ( P>0.05), indicating a potential decrease in attentional response speed. However, the moderate-to-severe group demonstrated significantly shorter P300 latencies [CZ-S1(394.18±89.12) ms] compared to the mild group [CZ-S1 (433.33±100.33) ms] ( F=3.145, P<0.05), possibly reflecting compensatory enhancement of attentional engagement in more severe cases. Conclusion:Children with OSDB exhibit impairments in primary visual processing and attentional regulation, as evidenced by altered ERP components such as P100 and P300. These findings suggest that OSDB may affect neural mechanisms underlying sensory integration and executive functioning.

ObjectiveTo investigate the mechanism of topical treatment of allergic contact dermatitis （ACD） mice with Portulacae Herba based on the nuclear factor E₂-related factor 2 （Nrf2）/heme oxygenase-1 （HO-1）/nuclear factor-κB （NF-κB） signaling pathway. MethodsA total of 70 6-week-old specific pathogen free （SPF） female Kunming mice were adaptively fed for 1 week and randomly divided into blank group， model group， compound dexamethasone acetate cream group （2.075×10^-2 g·g^-1）， blank matrix cream group， low-dose Portulacae Herba cream group （0.1 g·g^-1）， high-dose Portulacae Herba cream group （0.2 g·g^-1）， and Portulacae Herba + inhibitor group （0.2 g·g^-1 + 30 mg·kg^-1 ML385）， with 10 mice in each group. One day before the experiment， the mice were shaved on the neck and back. Except for the blank group， the mice in the other groups were treated with 2，4-dinitrochlorobenzene （DNCB） to establish an ACD model. After respective administration， the skin lesion of the mice was scored， and the histopathological changes of the skin were stained with hematoxylin-eosin （HE）. Enzyme-linked immunosorbent assay （ELISA） was used to detect the levels of interleukin-6 （IL-6）， interleukin-1β （IL-1β）， reactive oxygen species （ROS）， superoxide dismutase （SOD） activity， and malondialdehyde （MDA） in serum of mice. The expression of Nrf2/HO-1/NF-κB signaling pathway-related proteins in mouse skin tissue was detected by immunohistochemistry （IHC）， Western blot， and real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. ResultsCompared with the blank group， the mice in the model group had an increased skin lesion score （P<0.01）， severe pathological damage to skin tissue， increased content of IL-1β， IL-6， ROS， and MDA in their serum （P<0.01）， and decreased content of SOD （P<0.01）. In addition， the mRNA and protein expression levels of Nrf2， HO-1， and nuclear factor-κB inhibitor α （IκBα） in skin tissue were up-regulated （P<0.01）， while the protein expression levels of phosphorylated （p）-IκBα and p-NF-κB p65 and the mRNA expression of NF-κB p65 were down-regulated （P<0.01）. Compared with the model group and the blank matrix cream group， the mice treated with Portulacae Herba had a decreased skin lesion score （P<0.01）， reduced pathological damage to skin tissue， decreased content of IL-1β， IL-6， ROS， and MDA in their serum （P<0.01）， and increased content of SOD （P<0.01）. Additionally， the mRNA and protein expression levels of Nrf2， HO-1， and IκBα in skin tissue were down-regulated （P<0.05，P<0.01）， and the protein expression levels of p-IκBα and p-NF-κB p65 and the mRNA expression of NF-κB p65 were up-regulated （P<0.05，P<0.01）. Compared with the Portulacae Herba + inhibitor group， the high-dose Portulacae Herba cream group had a decreased skin lesion score （P<0.01）， alleviated pathological damage to skin tissue， decreased content of IL-1β， IL-6， ROS， and MDA in the serum of mice （P<0.05，P<0.01）， and increased content of SOD （P<0.01）. The protein expression levels of Nrf2， HO-1， and IκBα and the mRNA expression of Nrf2 and HO-1 in skin tissue were up-regulated （P<0.05，P<0.01）， and the protein expression levels of p-IκBα and p-NF-κB p65 and the mRNA expression of NF-κB p65 were down-regulated （P<0.05）. ConclusionPortulacae Herba can improve DNCB-induced ACD skin damage in mice by regulating the Nrf2/HO-1/NF-κB signaling pathway.

INTRODUCTION: Lecanemab has shown promise in treating early Alzheimer's disease (AD), but its safety and efficacy in Chinese populations remain unexplored. This study aimed to evaluate the safety and 6-month clinical outcomes of lecanemab in Chinese patients with mild cognitive impairment (MCI) or mild AD. METHODS: In this single-arm, real-world study, participants with MCI due to AD or mild AD received biweekly intravenous lecanemab (10 mg/kg). The study was conducted at Hainan Branch, Ruijin Hospital Shanghai Jiao Tong University School of Medicine. Patient enrollment and baseline assessments commenced in November 2023. Safety assessments included monitoring for amyloid-related imaging abnormalities (ARIA) and other adverse events. Clinical and biomarker changes from baseline to 6 months were evaluated using cognitive scales (mini-mental state examination [MMSE], montreal cognitive assessment [MoCA], clinical dementia rating-sum of boxes [CDR-SB]), plasma biomarker analysis, and advanced neuroimaging. RESULTS: A total of 64 patients were enrolled in this ongoing real-world study. Safety analysis revealed predominantly mild adverse events, with infusion-related reactions (20.3%, 13/64) being the most common. Of these, 69.2% (9/13) occurred during the initial infusion and 84.6% (11/13) did not recur. ARIA-H (microhemorrhages/superficial siderosis) and ARIA-E (edema/effusion) were observed in 9.4% (6/64) and 3.1% (2/64) of participants, respectively, with only two symptomatic cases (one ARIA-E presenting with headache and one ARIA-H with visual disturbances). After 6 months of treatment, cognitive scores remained stable compared to baseline (MMSE: 22.33 ± 5.58 vs . 21.27 ± 4.30, P = 0.733; MoCA: 16.38 ± 6.67 vs . 15.90 ± 4.78, P = 0.785; CDR-SB: 2.30 ± 1.65 vs . 3.16 ± 1.72, P = 0.357), while significantly increasing plasma amyloid-β 42 (Aβ42) (+21.42%) and Aβ40 (+23.53%) levels compared to baseline. CONCLUSIONS: Lecanemab demonstrated a favorable safety profile in Chinese patients with early AD. Cognitive stability and biomarker changes over 6 months suggest potential efficacy, though high dropout rates and absence of a control group warrant cautious interpretation. These findings provide preliminary real-world evidence for lecanemab's use in China, supporting further investigation in larger controlled studies. REGISTRATION ClinicalTrials.gov , NCT07034222.
Humans ; Alzheimer Disease/drug therapy* ; Male ; Female ; Aged ; Middle Aged ; Cognitive Dysfunction/drug therapy* ; Aged, 80 and over ; Amyloid beta-Peptides/metabolism* ; Biomarkers ; East Asian People

Nine novel compounds, comprising seven tetrahydroanthraquinones (auxarthrolones A-G, 1-7), a γ-butenolide glycoside (malfilamentoside E, 26), and a γ-butenolide (auxarthrolide A, 27), together with eighteen known compounds (8-25) were isolated from rice-based solid culture of Auxarthron umbrinum (A. umbrinum) DSM3193 using the one strain many compounds (OSMAC) approach. The structural elucidation of these compounds was accomplished through nuclear magnetic resonance (NMR), mass spectrometry (MS), and NMR calculation combined with DP4+ analysis or MAEΔΔδ parameter, while the absolute configurations of new compounds were established through single-crystal X-ray diffraction, electronic circular dichroism (ECD) spectroscopic data analysis and/or chemical derivatization. Austrocortilutein (10) and auxarthrol H (14) demonstrated moderate cytotoxicity against U87 and U251 [half maximal inhibitory concentration (IC₅₀) 3.5-12.1 μmol·L^-1]. Additionally, auxarthrolone A (1), auxarthrol H (14), eupolyphagin B (15), and 7-hydroxy-2-(2-hydroxypropyl)-5-methylchromone (17) exhibited torsional effects on fibroblast proliferation challenges induced by oleic acid, thus demonstrating fibroblast proliferation-promoting activity.
4-Butyrolactone/pharmacology* ; Molecular Structure ; Anthraquinones/pharmacology* ; Humans ; Animals ; Mice ; Cell Line, Tumor ; Magnetic Resonance Spectroscopy

OBJECTIVE To study the effects and mechanism of Portulaca oleracea cream on skin pruritus and barrier function in allergic contact dermatitis （ACD） mice. METHODS Low-concentration and high-concentration P. oleracea creams were prepared， with the P. oleracea extract solution （1 g/mL， calculated by crude drug） concentrations of 10% and 20%. Sixty BALB/c mice were randomly allocated into blank group， model group， Mometasone furoate cream group （positive control）， blank matrix cream group， P. oleracea low-concentration and high-concentration cream groups. Except for blank group， ACD model was induced in each group using 2，4-dinitrochlorobenzene solution. The blank group and model groups received normal saline， while the remaining groups were treated with their respective creams， once a day， at a dose of approximately 0.5 g per application， continuously for 14 days. At 24 h post-final administration， skin lesions of mice were observed and scored； pathological changes of skin tissue were observed； serum levels of immunoglobulin E（IgE） and tumor necrosis factor-α （TNF-α） were quantified. mRNA expression of MAS-related G protein-coupled receptors （including MrgprA3， MrgprC11， and MrgprD） in dorsal root ganglion （DRG） was assessed； while protein expressions of skin barrier function-related proteins Claudin-1 and Occludin in skin tissues were determined. RESULTS Compared with blank group， mice in the model group exhibited severe skin damage， characterized by loss of epidermal architecture， hyperkeratosis of the skin tissue， and the infiltration of a large number of inflammatory cells. The skin injury scores， as well as the serum levels of IgE and TNF-α， and the mRNA expression levels of MrgprA3， MrgprC11， and MrgprD in DRG， were all significantly elevated compared to the blank group （P＜0.05 or P＜0.01）； in contrast， the protein expression levels of Claudin-1 and Occludin in the skin tissue were markedly reduced （P＜0.05）. Compared with model group， mice in P. oleracea low-concentration and high- concentration cream groups demonstrated significant alleviation of skin damage， as evidenced by reduced epidermal hyperplasia， mitigated spongiosis in the dermis， and decreased infiltration of inflammatory cells； these quantitative indicators were almost significantly reversed （P＜0.05 or P＜0.01）. No significant differences were observed in the aforementioned skin injuries， pathological alterations， or quantitative indicators between the blank matrix cream group and the model group. CONCLUSIONS P. oleracea may ameliorate skin lesions and restore skin barrier function of ACD mice， the mechanism of which may be associated with downregulating mRNA expressions of MrgprA3， MrgprC11 and MrgprD in DRG， and up-regulating the protein expressions of Claudin-1 and Occludin in skin tissue.

Efficacy evaluation of TCM syndromes is a core aspect of validating the clinical effectiveness of TCM.However,consensus has yet to be established regarding its conceptual definition,measurement tools,and methodological framework.This article reviewed the current state of research in TCM syndrome efficacy evaluation:Conceptually,there is a need to clarify the distinction between broad(encompassing all outcome measures highlighting the efficacy of treatment based on syndrome differentiation)and narrow(limited to syndrome-related indicators)definitions;in terms of content and methodology,it is essential to integrate macro-and micro-level indicator systems,standardize evaluation models that either combine or separate disease and syndrome diagnosis,and address the characteristics of dynamism,individualization,and holism;regarding measurement,challenges such as interference from disease factors and insufficient indicator matching persist in the development of scales,objectification of the four diagnostic methods(inspection,listening and smelling,inquiry,pulse-taking),and construction of mathematical models still exist.Future research directions may focus on the following:Enhancing a people-centered evaluation process through"co-construction by practitioners and patients";Establishing a primary framework centered on"guiding disease treatment by syndrome differentiation"to promote the quantification and precision of syndrome indicators(e.g.,state-target syndrome differentiation);Integrating multiple data sources to construct an evidence-based comprehensive evaluation system.By standardizing definitions,innovating tools,and integrating methodologies,the standardization and precision of TCM pattern efficacy evaluation research can be advanced.

Objective:To study the correlation between iodine level in drinking water and conventional water quality indicators.Methods:From June 2017 to July 2018, a simple random sampling method was used to select administrative villages (communities) from 88 counties (cities, districts) in Guizhou Province with a sampling size greater than 5%. One drinking water sample was collected from each administrative village (community), and conventional water quality indicators (including fluorine, aluminum, mercury, selenium, sulfate, total dissolved solids and total hardness) were tested in accordance with the methods outlined in the "Standards for Drinking Water Quality" (GB 5749-2006). The cerium sulfate catalytic spectrophotometric method was employed to test drinking water iodine level. Spearman method was utilized to analyze the correlation between iodine level in drinking water and conventional water quality indicators.Results:A total of 904 drinking water samples were tested, with a median iodine level of 1.90 μg/L and a range of 0.10 - 36.70 μg/L. There were 899 administrative villages (communities) with a water iodine level of less than 10 μg/L, accounting for 99.45%. There were only 5 administrative villages (communities) with a water iodine level of greater than 10 μg/L, accounting for 0.55%. Correlation analysis revealed that in Guizhou Province, the iodine level in drinking water was positively correlated with the levels of fluorine, aluminum, sulfate, total dissolved solids, and total hardness [correlation coefficients ( r) = 0.11, 0.07, 0.07, 0.08, 0.07, P < 0.05], and was a negatively correlated with mercury and selenium levels ( r = - 0.12, - 0.12, P < 0.001). Conclusions:External environment in Guizhou Province is generally deficient in iodine. The iodine level in drinking water is positively correlated with the levels of fluorine, aluminum, sulfate, total dissolved solids, and total hardness, and negatively correlated with the levels of mercury and selenium.

Objective To investigate the therapeutic effect of folic acid combined with decitabine in diabetic retinop-athy(DR)mice with different methylenetetrahydrofolate reductase(MTHFR)genotypes.Methods The DR model mice were created by mating 20 MTHFR-/-mice with 20 wild-type C57 mice.A random number table method was employed to allocate 20 successfully modelled mice into the model group,DAC group,FA group,and FA+DAC group,with five mice assigned to each group.Five untreated MTHFR-/-and wild-type mice served as normal control.After constructing the DR model,the DAC group was injected intraperitoneally with 0.25 mg·kg-1 decitabine once every 5 days;the FA group was given 70 μg·kg-1 folic acid by tube feed once a day;the FA+DAC group was given 0.25 mg·kg-1 decitabine and 70μg·kg-1 folic acid at the same time;and the normal group was given an equal amount of physiological saline.All of the above groups were intervened for 30 days.OCT was employed for the measurement of retinal thickness,OCTA for retinal vascular density,histopathology(HE staining)for pathological changes in the mouse retina,real-time fluorescence quanti-tative PCR for mRNA expression,and Western blot analysis for protein expression levels.Results Compared with the wild-type model group,the degree of increase in retinal thickness and vascular density in the retinal layer was more pro-nounced in the MTHFR-/-mice model group(all P＜0.05).In wild-type mice,retinal thickness and retinal layer vessel den-sity were reduced in the DAC,FA and FA+DAC groups compared to the model group,with the FA+DAC group show-ing the greatest degree of reduction.The differences were all statistically significant(all P＜0.05);In MTHFR-/-mice,reti-nal thickness and vascular density in the retinal layer were reduced in the DAC group and the FA+DAC group compared to the model group(allP＜0.05).HE staining results showed an increased extent of retinal damage in the MTHFR-/-mice model group compared with the wild-type mice model group.Compared with the model group,the DAC group and the FA+DAC group had thinner retinas and more aligned ganglion cell layers in all types of mice,with the FA group having a worse effect and the FA+DAC group having a better treatment effect.The results of the polymerase chain reaction(PCR)revealed that the relative expression of the SAHH,MAT2A and DNMT1 proteins in the retinal tissues of the wildtype and MTHFR-/-mice model groups was elevated in comparison to the control group(all P＜0.05).Furthermore,the relative mR-NA expression of the DAC,FA and FA+DAC groups was reduced in comparison to the model group(all P＜0.05).In wild-type mice,the relative expression of MTHFR protein mRNA was decreased in the model group compared with the con-trol group,and increased in the DAC group,FA group,and FA+DAC group compared with the model group(all P＜0.05).Western blot results showed that the relative expression of DNMT1,MAT2A and SAHH proteins in the retinal tissues of the wild-type and MTHFR-/-mice model groups was higher than that of the control group(all P＜0.05),and the relative expression was lower in the DAC,FA,and FA+DAC groups compared with that in the model group(all P＜0.05).In wild-type mice,the relative expression of MTHFR protein in the retinal tissue of the model group was lower than that of the control group,and the relative expression of MTHFR protein in the FA group and the FA+DAC group was elevated com-pared with that of the model group(all P＜0.05).Conclusion The protective effect of folic acid combined with decit-abine on DR was superior to that of decitabine alone;treatment with folic acid in combination with decitabine may have yielded better efficacy in wild-type DR mice.