ObjectiveTo investigate the mechanisms of Runmu Dihuang decoction （RMDHD） in treating perimenopausal dry eye with liver-kidney Yin deficiency syndrome based on the silent information regulator 3 （SIRT3）/hypoxia-inducible factor-1α （HIF-1α）/nuclear factor-κB （NF-κB） signaling pathway. MethodsSixty female Sprague-Dawley rats were randomly divided into six groups （n=10 per group）： Sham operation group， model group， sodium hyaluronate eye drop group， and low-， medium-， and high-dose RMDHD groups （5.625， 11.25， 22.50 g·kg^-1）. Except for the sham operation group， all rats underwent bilateral ovariectomy and were administered 0.1% benzalkonium chloride eye drops combined with long-term chronic irritation to establish a perimenopausal dry eye model with liver-kidney Yin deficiency syndrome. Drug administration began in the 11th week after modeling and continued for 21 days. General conditions， screen-grip test scores， tear secretion volume， tear film breakup time （TFBUT）， and corneal fluorescein staining were recorded. Serum levels of reactive oxygen species （ROS）， follicle-stimulating hormone （FSH）， estradiol （E₂）， and progesterone （PROG） were measured by enzyme-linked immunosorbent assay （ELISA）. Pathological changes in the lacrimal glands， corneas， and uteri were observed using hematoxylin-eosin （HE） staining. Protein expression levels of SIRT3， HIF-1α， phosphorylated NF-κB p65 （p-NF-κB p65）， and total NF-κB p65 in the lacrimal glands were detected by Western blot. The expression of inflammatory cytokines interleukin-1β （IL-1β） and tumor necrosis factor-α （TNF-α） in the lacrimal glands was assessed by immunohistochemistry （IHC）. ResultsAfter model establishment， no significant differences were observed among the groups except the sham operation group. Compared with the sham operation group， the other groups exhibited slowed movement， dull responses， increased irritability， reduced body weight， elevated rectal temperature， decreased screen-grip test scores， reduced tear secretion， and significantly shortened TFBUT （P<0.05）. After treatment， compared with the model group， the sodium hyaluronate eye drop group and all RMDHD groups showed improved general conditions， significantly increased tear secretion （P<0.05）， prolonged TFBUT （P<0.05）， and elevated screen-grip test scores （P<0.05）. Serum ROS and FSH levels were significantly decreased， while E₂ and PROG levels were significantly increased （P<0.05）. Pathological damage to the cornea， lacrimal glands， and uterus was ameliorated. In addition， protein expression levels of SIRT3 and HIF-1α in the lacrimal glands were significantly upregulated （P<0.05）， whereas the expression of p-NF-κB p65， IL-1β， and TNF-α was significantly downregulated （P<0.05）. ConclusionRMDHD increases tear secretion and TFBUT， improves lacrimal gland and corneal injury， and alleviates dry eye symptoms in a perimenopausal dry eye rat model with liver-kidney Yin deficiency syndrome. The underlying mechanism may be related to regulation of the SIRT3/HIF-1α/NF-κB signaling pathway， inhibition of oxidative stress and inflammatory responses， and reduction of ocular surface tissue damage.

Objective Magnetoreception, the remarkable ability of diverse animals to sense and utilize the geomagnetic field for orientation and navigation, remains a molecularly unresolved mystery in sensory biology. The putative magnetoreceptor (MagR, previously known as IscA1) is a highly conserved iron-sulfur protein implicated in both magnetoreception and iron metabolism; however, the functional diversity among its cross-species homologs remains poorly understood. Cellular morphology is a key genetically determined trait that can be altered through genetic or environmental modifications—a process known as cell morphology engineering. Constructing engineered cells with specific morphological features and magnetic sensitivity to achieve remote, non-invasive magnetic modulation represents a crucial goal in this field with significant application potential. Therefore, this study aims to systematically investigate the effects of MagR heterologous expression on bacterial morphology and magnetic sensing capabilities, screen for MagR-based magnetically sensitive morphology engineering pathways, and reveal the underlying molecular mechanisms. Methods We systematically screened 28 MagR homologous genes from diverse prokaryotic and animal taxa to evaluate their expression and corresponding phenotypic effects in Escherichia coli (E. coli). To compare the differential magnetic responses among bacteria expressing various recombinant MagR proteins, we utilized high-throughput automated bright-field microscopic imaging and scanning electron microscopy (SEM). Furthermore, comprehensive biochemical and biophysical characterizations of iron and iron-sulfur cluster binding were performed using Ferrozine colorimetric assays, electron paramagnetic resonance (EPR) spectroscopy, ultraviolet-visible (UV-Vis) absorption, and circular dichroism (CD) spectroscopy. Additionally, 100 mT static magnetic field (SMF) exposure experiments were conducted to assess magnetically tunable phenotypes, while the intrinsic magnetic properties of purified MagR proteins were directly measured using a superconducting quantum interference device (SQUID) magnetometer. Results Our results demonstrated that the heterologous expression of MagR homologs induced varying degrees of bacterial filamentation. From this comprehensive screen, two distinct morphological patterns were identified: hydra (Hydra vulgaris) MagR (hyMagR) promoted uniform cell elongation and filamentation, exhibiting robust magnetic sensitivity manifested as significantly enhanced filamentation under the 100 mT SMF. In contrast, pigeon (Columba livia) MagR (clMagR) induced only low-frequency, extreme filamentation (sporadically exceeding 80 μm) with a relatively weaker magnetic morphological response. Mechanistically, our data unambiguously proved that these phenotypic differences are primarily driven by distinct iron redox preferences rather than total cellular iron accumulation. Specifically, hyMagR preferentially binds ferrous iron (Fe²⁺), whereas clMagR favors ferric iron (Fe³⁺) and forms more stable iron-sulfur clusters. Intriguingly, although SQUID magnetometry showed that purified clMagR exhibited approximately five-fold higher mass magnetic susceptibility than hyMagR, its cellular magnetic response was weaker. We hypothesize that the Fe²⁺-preferred intracellular environment associated with hyMagR overexpression primes the cell for enhanced generation of reactive oxygen species (ROS) via the Fenton reaction. Exposure to an SMF synergizes with this primed redox state, triggering the bacterial SOS response and upregulating cell division inhibitors to efficiently induce uniform filamentation. Conclusion Our findings identify the Fe²⁺/Fe³⁺ redox state as a critical determinant of MagR-mediated morphological remodeling and magnetic responsiveness. This discovery suggests a potential strategy for engineering magnetically responsive cellular systems for synthetic biology applications, and provides a plausible framework, which potentially combines intrinsic protein magnetism with redox-state modulation, for further investigating the evolutionary mechanisms of MagR-mediated magnetoreception.

Objective Magnetoreception, the remarkable ability of diverse animals to sense and utilize the geomagnetic field for orientation and navigation, remains a molecularly unresolved mystery in sensory biology. The putative magnetoreceptor (MagR, previously known as IscA1) is a highly conserved iron-sulfur protein implicated in both magnetoreception and iron metabolism; however, the functional diversity among its cross-species homologs remains poorly understood. Cellular morphology is a key genetically determined trait that can be altered through genetic or environmental modifications—a process known as cell morphology engineering. Constructing engineered cells with specific morphological features and magnetic sensitivity to achieve remote, non-invasive magnetic modulation represents a crucial goal in this field with significant application potential. Therefore, this study aims to systematically investigate the effects of MagR heterologous expression on bacterial morphology and magnetic sensing capabilities, screen for MagR-based magnetically sensitive morphology engineering pathways, and reveal the underlying molecular mechanisms. Methods We systematically screened 28 MagR homologous genes from diverse prokaryotic and animal taxa to evaluate their expression and corresponding phenotypic effects in Escherichia coli (E. coli). To compare the differential magnetic responses among bacteria expressing various recombinant MagR proteins, we utilized high-throughput automated bright-field microscopic imaging and scanning electron microscopy (SEM). Furthermore, comprehensive biochemical and biophysical characterizations of iron and iron-sulfur cluster binding were performed using Ferrozine colorimetric assays, electron paramagnetic resonance (EPR) spectroscopy, ultraviolet-visible (UV-Vis) absorption, and circular dichroism (CD) spectroscopy. Additionally, 100 mT static magnetic field (SMF) exposure experiments were conducted to assess magnetically tunable phenotypes, while the intrinsic magnetic properties of purified MagR proteins were directly measured using a superconducting quantum interference device (SQUID) magnetometer. Results Our results demonstrated that the heterologous expression of MagR homologs induced varying degrees of bacterial filamentation. From this comprehensive screen, two distinct morphological patterns were identified: hydra (Hydra vulgaris) MagR (hyMagR) promoted uniform cell elongation and filamentation, exhibiting robust magnetic sensitivity manifested as significantly enhanced filamentation under the 100 mT SMF. In contrast, pigeon (Columba livia) MagR (clMagR) induced only low-frequency, extreme filamentation (sporadically exceeding 80 μm) with a relatively weaker magnetic morphological response. Mechanistically, our data unambiguously proved that these phenotypic differences are primarily driven by distinct iron redox preferences rather than total cellular iron accumulation. Specifically, hyMagR preferentially binds ferrous iron (Fe²⁺), whereas clMagR favors ferric iron (Fe³⁺) and forms more stable iron-sulfur clusters. Intriguingly, although SQUID magnetometry showed that purified clMagR exhibited approximately five-fold higher mass magnetic susceptibility than hyMagR, its cellular magnetic response was weaker. We hypothesize that the Fe²⁺-preferred intracellular environment associated with hyMagR overexpression primes the cell for enhanced generation of reactive oxygen species (ROS) via the Fenton reaction. Exposure to an SMF synergizes with this primed redox state, triggering the bacterial SOS response and upregulating cell division inhibitors to efficiently induce uniform filamentation. Conclusion Our findings identify the Fe²⁺/Fe³⁺ redox state as a critical determinant of MagR-mediated morphological remodeling and magnetic responsiveness. This discovery suggests a potential strategy for engineering magnetically responsive cellular systems for synthetic biology applications, and provides a plausible framework, which potentially combines intrinsic protein magnetism with redox-state modulation, for further investigating the evolutionary mechanisms of MagR-mediated magnetoreception.

Background: High-mobility group box protein 1 (HMGB1) is a chromatin-binding protein involved in arthritis, ischemia, sepsis, atherosclerosis, neurodegenerative disorders, meningitis, and cancer. HMGB1 exhibits dual roles in cancer, acting as either a tumor suppressor or oncoprotein depending on context. Objective: This research aimed to elucidate HMGB1’s functional significance in cutaneous squamous cell carcinoma (cSCC). Methods: We overexpressed HMGB1 in cSCC cell lines using recombinant adenovirus and examined its effects on cell proliferation, colony formation, and cell migration. Results: Immunohistochemical analysis revealed elevated HMGB1 expression levels in cSCC tissue relative to normal epidermis. To assess the influence of HMGB1, we employed recombinant adenoviruses expressing HMGB1 to transduce SCC cell lines (SCC12 and SCC13). Enhanced HMGB1 expression significantly promoted cellular proliferation and colony formation capacity.Notably, HMGB1 overexpression elevated the levels of proliferation regulators, including P63, SOX2, CDK4 and CDK6. Furthermore, HMGB1 overexpression substantially enhanced tumor invasiveness, accompanied by upregulation of epithelial-mesenchymal transition (EMT) biomarkers. Mechanistically, overexpression of HMGB1 enhanced transforming growth factor-β signaling by increasing phosphorylation of SMAD2/3, the key mediators of EMT. Conclusion These data imply that HMGB1 acts as a tumor-promoting factor in cSCC.

Background: and Purpose Vertebrobasilar fusiform aneurysms (VBFAs) carry substantial morbidity and mortality, but optimal management for unruptured VBFAs remains unclear. We compared the safety and efficacy of conservative management (CM), stent-assisted coiling (SAC), and flow diverters (FDs) in patients with unruptured VBFAs, focusing on long-term prognosis. Methods: This study included data from a nationwide Chinese cohort of patients with vertebrobasilar dissecting aneurysms. Inverse probability of treatment weighting (IPTW) balanced confounders across groups. The primary outcome was poor prognosis (modified Rankin Scale score >2). Secondary outcomes included aneurysm rupture, ischemic stroke, compression symptoms, and VBFA-related deaths. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were performed. Results: Among 1,115 patients with unruptured VBFAs, 838 (median age, 54 years; 655 men) were included. After IPTW, baseline characteristics were balanced. Median follow-up was 54 months. FD was associated with a lower risk of poor prognosis than CM (OR, 0.48 [95% CI, 0.30 to 0.77]; p=0.002), with no difference between CM and SAC. FD also reduced aneurysm rupture (OR, 0.20 [95% CI, 0.07 to 0.60]; p=0.004) and compression symptoms (OR, 0.30 [95% CI, 0.13 to 0.68]; p=0.004) versus CM. Time-to-event analyses further revealed significant differences in vertebral artery lesions and Type I–II VBFAs, whereas no significant differences were observed in basilar or vertebrobasilar junction lesions or in Type III–IV VBFAs. Conclusions Compared with CM, FD was associated with improved long-term outcomes in unruptured VBFAs, particularly in vertebral artery lesions and Type I–II VBFAs, although residual confounding cannot be excluded.

China has become the country with the highest global burden of heart failure(HF).Despite the widespread use of prognostic-improving medications today,the mortality rate of HF remains high,reaching 13.7％at one year-particularly among patients with heart failure with reduced ejection fraction(HFrEF).HF interventional device therapy(structural intervention)targets the structural factors underlying HF,including atrial pressure,ventricular remodeling,and valvular intervention.It leverages the heart's intrinsic physiological properties and pathological progression mechanisms to deliver treatments through interventions without external active forces,achieving anatomical or functional repair.This field has emerged as a rapidly growing area and plays an increasingly critical role in HF management.This article provides a comprehensive review and summary of the latest advancements in HF and cardiomyopathy interventional therapy over the past year.It covers various novel technologies and products currently in the research phase,aiming to provide an in-depth analysis of the current status and future directions of HF interventional therapy,and further advance the development of this discipline.

Aim To investigate the effect of chrysoeriol on pulmonary vascular remodeling in pulmonary hyper-tension by animal experiments combined with cell ex-periments,and to explore its potential therapeutic tar-gets by network pharmacology.Methods The target of chrysoeriol was collected in Targetnet,SEA and SwissTargetPrediction database.Pulmonary arterial hy-pertension(PAH)targets were collected in the Dis-GeNET and GeneCards databases,and PPI network map was drawn in the STRING database,and key tar-gets were screened.The GO and KEGG pathway en-richment analysis was carried out through DAVID data-base and Weishengxing platform.AutoDock software was used for molecular docking of key core targets.The PAH model of rats was constructed,and the pulmo-nary hemodynamics and vascular remodeling were de-tected by echocardiography,HE and Masson staining.Primary pulmonary smooth muscle cells were extracted,and the effects of drugs on pathway proteins were de-tected in vitro.Results The results of network phar-macology showed that chrysoeriol exerted therapeutic effects on pulmonary hypertension by affecting key tar-gets such as AKT1,SRC,EGFR,MMP9 and gsk3 β,and signaling pathways such as EGFR and PI3K-AKT.Molecular docking showed that chrysoeriol had good binding ability with 5 key target genes.Animal experi-ments showed that the pulmonary hemodynamic func-tion of PAH rats was significantly improved after ad-ministration of chrysoeriol.The remodeling of small pulmonary arteries was significantly reduced.Cell ex-periments showed that chrysoeriol could inhibit the ex-pression of proliferation,migration and phenotypic transformation genes.Conclusion Chrysoeriol may play a role in the treatment of pulmonary hypertension through multiple targets.

Objective To analyze the whole-brain structural-functional coupling imaging characteristics of patients with cerebral small vessel disease(CSVD)based on multiparametric functional and structural MRI,and to explore their correlation with cognitive function.Methods A prospective,consecutive study enrolled 60 CSVD patients from the Department of Neurology,the Second Affiliated Hospital of Anhui Medical University,between May 2021 and December 2023,and 47 controls matched for age,sex,education level,and handedness recruited from the community during the same period.Baseline data,including demographic information(age,sex,education),cognitive function,and imaging data,were collected for both groups.All participants underwent standardized neuropsychological assessments in a quiet environment.Emotional function was assessed using the patient health questionnaire-9(PHQ-9).Global cognitive function was screened using the Montreal cognitive assessment scale(MoCA)and Alzheimer's disease 8-item questionnaire(AD-8).Executive function was evaluated using the trail making test-B(TMT-B),the TMT time difference(TMT-B time minus TMT-A time),and the verbal fluency test(VFT).Attention and processing speed were assessed using TMT-A and the digit span test(DS).Memory function was evaluated using the Chinese auditory verbal learning test(AVLT),including learning,immediate recall,and delayed recall.Multimodal brain functional and structural MRI images were acquired for all participants.Fractional amplitude of low-frequency fluctuations(fALFF)and gray matter volume(GMV)were calculated using the DPABI software.A structure-function coupling index was computed by integrating the fALFF and GMV values of corresponding voxels.Structural-function coupling changes in CSVD patients and controls were assessed,and the correlations between fALFF,GMV,fALFF/GMV and cognitive function were explored.Results(1)Compared to the control group,CSVD patients showed significant lower scores in MoCA score(21.5[20.0,24.0]vs.24.3[23.0,26.0],Z=-4.094),higher PHQ-9 score(5.4±5.0vs.2.1±2.2,t=4.150),less VFT(15.5±3.8 vs.17.2±4.3,t=-3.258),increased TMT-B time([164.4±72.7]s vs.[123.6±45.7]s,t=3.307),TMT-A time([83.8±34.3]s vs.[62.9±22.7]s,t=3.704),and less DS forward span(6.3[5.0,8.0]vs.7.4[6.0,8.0],Z=-3.679),DS backward span(3.7±1.2 vs.4.5±1.4,t=-3.119),AVLT-learning(7.0±1.8 vs.8.7±1.9,t=-4.523),A VLT-immediate recall(7.2[6.0,9.0]vs.9.6[7.2,11.8],Z=-4.105),AVLT-delayed recall(6.9±3.1 vs.9.6±3.0,t=-4.310;all P＜0.01).No significant differences were observed in age,education,sex,AD-8 score,or TMT time difference(all P＞0.05).(2)CSVD patients showed decreased fALFF values in the right anterior cingulate gyrus(1.00±0.06 vs.1.07±0.06,t=-4.66)and increased fALFF values in the left superior parietal lobule(1.14±0.07 vs.1.07±0.07,t=5.68)and the right postcentral gyrus(1.08±0.05 vs.1.01±0.05,t=5.22;both P＜0.01).CSVD patients had increased GMV in the bilateral caudate nucleus(right:[0.27±0.06]mm3 vs.[0.21±0.04]mm3,t=6.12,left:[0.27±0.05]mm3 vs.[0.22±0.04]mm3,t=6.67;both P＜0.01)but decreased fALFF/GMV in the bilateral caudate nucleus(left:6.27±0.97 vs.7.75±1.70,t=-7.33;right:3.12±0.97 vs.4.18±0.95,t=-5.96)and the right globus pallidus(14.11±4.14 vs.19.99±4.03,t=-6.36;all P＜0.01).(3)Right anterior cingulate gyrus fALFF positively correlated with DS backward scores(R=0.348,P=0.013).Left superior parietal lobule fALFF negatively correlated with PHQ-9 scores(R=-0.308,P=0.029)and TMT time difference(R=-0.360,P=0.012).Right postcentral gyrus fALFF negatively correlated with TMT-A time(R=-0.419,P=0.003).Right caudate nucleus GMV positively correlated with TMT time difference(R=0.293,P=0.042),while left caudate nucleus GMV negatively correlated with AD-8 score(R=-0.284,P=0.043).fALFF/GMV in the right caudate nucleus(R=0.288,P=0.046)and right globus pallidus(R=0.290,P=0.045)positively correlated with VFT.After multiple comparison corrections,only the negative correlation between right postcentral gyrus fALFF and TMT-A time remained significant(P(alse discovery rate adjusted=0.024).Conclusions CSVD patients exhibit significant structure-function decoupling values in bilateral caudate nucleus and right globus pallidus are reduced,and this reduction is associated with a decline in verbal fluency.The results of this study still need to be further validated in larger sample size studies.

Objective To explore the effects of different CO2 pneumoperitoneum pressures during surgery on overweight or obese patients with laparoscopic panhysterectomy in Trendelenburg position.Methods A total of 88 overweight or obese patients who underwent laparoscopic panhysterectomy were selected and randomly divided into the low-pressure group and the high-pressure group according to random number table method,with 44 patients in each group.All patients used CO2 as the pneumoperitoneum medium during surgery,with 10 mmHg of CO2 pneumoperitoneum pressure in the low-pressure group and 15 mmHg of CO2 pneumoperitoneum pressure in the high-pressure group.The operation-related indexes,respiratory indicators,nasopharyngeal temperature and adverse reactions of patients were compared between the two groups.Results There was no significant difference in the surgical time,blood loss,intraoperative infusion volume,incidence of organ injury,and laparotomy rate between the two groups(P>0.05).The recovery time of anesthesia of patients in the low-pressure group was shorter than that in the high-pressure group(P<0.05).At 30 minutes after the establishment of pneumoperitoneum,the peak airway pressure(Ppeak)and plateau pressure(Pplat)of patients in the high-pressure group were significantly higher than those in the low-pressure group(P<0.05),while the dynamic lung compliance(Cdyn)of patients in the high-pressure group was significantly lower than that in the low-pressure group(P<0.05).At 60 minutes after the establishment of pneumoperitoneum and the end of pneumoperitoneum,the nasopharyngeal temperature of patients in the high-pressure group were significantly lower than those in the low-pressure group(P<0.05).The incidences of intraoperative hypothermia and shivering in the high-pressure group were significantly higher than those in the low-pressure group(P<0.05).Conclusion Compared with 15 mmHg of CO2 pneumoperitoneum pressure,10 mmHg of CO2 pneumoperitoneum pressure on overweight or obese patients with laparoscopic panhysterectomy in Trendelenburg position does not increase surgical difficulty,and the patients has lower airway pressure,better lung compliance,fewer adverse reactions,and faster recovery,which can also avoid intraoperative hypothermia.

AIM:To explore the regulatory mecha-nism of pinoresinol diglucoside(PDG)on angiogen-esis during osteoporotic fracture healing in vivo and in vitro.METHODS:Fifty male C57BL/6J mice were randomly divided into five groups:normal group,model group,PDG 0.005,0.015 g/kg groups,and parathyroid hormone 1-34(PTH1-34)4×10-5 g/kg group.The osteoporotic fracture model of ovariec-tomized combined with femoral fracture was estab-lished,the PDG group was given intragastric admin-istration every other day and the PTH1-34 group was given subcutaneous injection of PTH1-34 every other day for 8 weeks.Micro-CT scanning,immunofluo-rescence and immunohistochemical staining were used to detect the related parameters and protein expressions.Human umbilical vein endothelial cells(HUVECs)were cultured,normal group,PDG 1,10,100 μmol/L groups and PTH1-341 ng/mL group were set up.CCK-8 assay,scratch experiment,tubule for-mation experiment,immunofluorescence and Western blot were used to detect the related pa-rameters and protein expressions.RESULTS:In vivo experiments found,compared with the normal con-trol group,a small amount of bone callus volume of fracture site were increased in the model control group,while BMD of non-callus site of femur,tra-becular bone fraction(BV/TV),trabecular thickness(Tb.Th)and trabecular number(Tb.N)were de-creased(P＜0.01),and trabecular separation(Tb.Sp)was increased(P＜0.01).The positive expression of vascular endothelial marker vascular endothelial markers(CD31)was decreased(P＜0.01).Compared with mice in the model control group,bone callus volume,index of BMD and BV/TV were increased in the PDG 0.005 g/kg group(P＜0.05),index of BMD,BV/TV,Tb.Th,Tb.N were increased,and index of Tb.Sp was decreased in the PDG 0.015 g/kg group(P＜0.05),the positive expression of CD31 was in-creased in the PDG administration groups(P＜0.01),the protein expressions of vascular endothelial growth factor(VEGF-A)(P＜0.01),Yes-associated protein 1(YAP1)(P＜0.01),PDZ-binding motif(TAZ)(P＜0.05)and TEA domain transcription factor 2(TEAD2)(P＜0.01)were increased in callus in the PDG 0.015 g/kg groups.Cell experiments found,compared with the normal control group,PDG groups promoted the proliferation,migration and tubule formation activity of HUVECs to varying de-grees(P＜0.05),at the same time,the expression of endothelial cadherin(E-cadherin)was decreased(P＜0.01),and VEGF-A,TEAD2,TAZ and YAP1 protein expression were increased(P＜0.05).CONCLUSION:PDG may accelerate osteoporotic fracture healing by promoting bone angiogenesis through regulat-ing Hippo signal pathway.