Metal-Phenolic Network-Coated Nanoparticles as Stabilizers for the Engineering of Pickering Emulsions with Bioactivity.

Pickering emulsions stabilized by functional nanoparticles (NPs) have received considerable attention for improving the physical stability and biological function of NPs. Herein, hydrophobic polyphenols were chosen as phenolic ligands to form metal-phenolic network (MPN) coatings on NPs (e.g., silica, polystyrene) mediated by the sono-Fenton reaction. The MPN coatings modulated the surface wettability and charges of NPs and achieved emulsification behavior for preparing Pickering emulsions with pH responsiveness and oxidation resistance. A series of polyphenols, including resveratrol, rutin, naringin, and curcumin, were used to form MPN coatings on NPs, which served as stabilizers for the engineering of functionalized oil-in-water (O/W) Pickering emulsions. This work provides a new avenue for the use of hydrophobic polyphenols to modulate NP emulsifiers, which broadens the application of polyphenols for constructing Pickering emulsions with antioxidant properties.

Particle-Polymer Union with Changeable Wettability for Constructing Bijels Using a Simple Mixing Method.

Bicontinuous emulsion gels (bijels) are nonequilibrium dispersed systems with particle-stabilized continuous fluid domains, and the internal connectivity of channels brings the possibility of efficient mass transport, endowing bijels great potential in diverse applications. Different from the common method to produce bijels, the spinodal decomposition, which needs precise temperature control and is restricted by the selection of liquid pairs, in this work, a direct mixing method was performed to construct bijels, simplifying the fabrication process. The hydrophilic rod-shaped cellulose nanocrystalline (CNC) particles were in situ combined with the hydrophobic polymer, aminopropyl-terminated polydimethylsiloxane (PDMS-NH2), to acquire a controllable interfacial wettability of CNC. The CNC@mPDMS-NH2 complexes were adsorbed at the water-toluene interface and achieved a change of Pickering emulsion types, oil-in-water, bijel, and water-in-oil, through tuning the interfacial performance of CNC@mPDMS-NH2 complexes. A three-dimensional scanning image and curvature calculation were applied to verify the obtained bijel, further demonstrating the successful preparation of the bicontinuous structure. This work enriched the members of particles for stabilizing bijels and was considered to be scalable in manufacturing for applications on a large scale.

Polymerizable bijels prepared by a direct-mixing method.

A simple direct-mixing method was proposed to use a union of silica particles and amino-capped silicone oil (diNH2-PDMS) as stabilizers to form bicontinuous emulsion gels (bijels) in wide mixing proportions of silica particle/diNH2-PDMS and oil/water with a tunable channel size of the spatial continuity, which was verified by the three-dimensional reconstruction viewer and curvature analysis. By direct polymerization of the oil phase as a template, solid materials were obtained with interconnected structures.

Developing Safe Organohydrogel Sunscreens Using Polyelectrolyte-Betaine Surfactant Complexes.

Oil-in-water emulsions are extensively used in skincare products due to their improved texture, stability, and effectiveness. There is limited success in developing effective delivery systems that can selectively target the active sunscreen ingredients onto the skin surface. Herein, an organohydrogel was prepared by physical cross-linking of an oil-in-water nanoemulsion with chitosan under neutral pH conditions. In the presence of a small quantity of coconut oil, lauramidopropyl betaine and glycerol were able to emulsify the active sunscreen ingredients into nanoscale droplets with enhanced ultraviolet light absorption. A facile pH-triggered interfacial cross-linking approach was applied to transform the nanoemulsion into an organohydrogel sunscreen. Furthermore, the organohydrogel sunscreen displayed encouraging characteristics including efficient UV-blocking capacity, resistance to water, simple removal, and minimal skin penetration. This facile approach provides an effective pathway for scaling up the organohydrogels, which are highly suitable for the safe application of sunscreen.

Biologically Derived Nanoarchitectonic Coatings for the Engineering of Hemostatic Needles.

Bleeding after venipuncture could cause blood loss, hematoma, bruising, hemorrhagic shock, and even death. Herein, a hemostatic needle with antibacterial property is developed via coating of biologically derived carboxymethyl chitosan (CMCS) and Cirsium setosum extract (CsE). The rapid transition from films of the coatings to hydrogels under a wet environment provides an opportunity to detach the coatings from needles and subsequently seal the punctured site. The hydrogels do not significantly influence the healing process of the puncture site. After hemostasis, the coatings on hemostatic needles degrade in 72 h without inducing a systemic immune response. The composition of CMCS can inhibit bacteria of Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus by destroying the membrane of bacteria. The hemostatic needle with good hemostasis efficacy, antibacterial property, and safety is promising for the prevention of bleeding-associated complications in practical applications.

Exosomes derived from menstrual blood stromal cells ameliorated premature ovarian insufficiency and granulosa cell apoptosis by regulating SMAD3/AKT/MDM2/P53 pathway via delivery of thrombospondin-1.

Premature ovarian insufficiency (POI) is clinically irreversible and seriously damages female fertility. We previously demonstrated that menstrual blood stromal cells (MenSCs)-derived exosomes (EXOs) effectively improved ovarian functions in the POI rat model. In this study, we investigated whether TSP1 is the key component in EXOs to ameliorate ovarian functions and further explored the molecular mechanism of EXOs in improving granulosa cell (GCs) activities. Our results demonstrated that knockdown TSP1 significantly debilitated the therapeutic effect of EXOs on estrous cyclicity, ovarian morphology, follicle numbers and pregnancy outcomes in 4-vinylcyclohexene diepoxide (VCD) induced POI rat model. In addition, EXOs treatment significantly promoted the activities and inhibited the apoptosis of VCD induced granulosa cells in vitro. Moreover, EXOs stimulation markedly activated the phosphorylation of SMAD3(Ser425) and AKT(Ser473), up-regulated the expressions of BCL2 and MDM2 as well as down-regulated the expressions of CASPASE3, CASPASE8, P53 and BAX. All these effects were supressed by SIS3, a inhibitor of TGF1/SMAD3. Our study revealed the key role of TSP1 in EXOs in improving POI pathology, restoring ovarian functions and GCs activities, andprovided a promising basis for EXOs in the treatment of ovarian dysfunction.

Clinical characteristics of hepatitis flares during pregnancy and postpartum in Chinese chronic hepatitis B virus carriers-a prospective cohort study of 417 cases.

Background: In China, it is common for pregnant women with a high load of hepatitis B virus (HBV) to take nucleos(t)ide analogue (NA) to prevent maternal-to-child transmission of HBV. However, the impact of NA intervention on virological and biochemical parameters in pregnant and postpartum women and the safety of drug cessation remain unclear. A prospective observational cohort was established in this study to analyze the clinical characteristics of hepatitis flares in pregnant and postpartum chronic HBV carriers, with or without NA intervention. Methods: Pregnant women who were chronic HBV carriers were enrolled in this study and divided into an NA intervention group and a non-intervention group according to their preferences. Liver function, HBV DNA level, and HBV serological markers were regularly measured during pregnancy and at approximately 6 weeks, 12 weeks, 24 weeks, 36 weeks, and 48 weeks postpartum. Results: A total of 417 patients were enrolled, including 303 in the NA intervention group and 114 in the non-intervention group. The incidence rates of postpartum hepatitis flares in both groups were higher than that of during pregnancy (45.7% vs 10.9%, p < 0.001; 41.2% vs 17.7%, p < 0.001). The second trimester was the peak of the incidence of flares during pregnancy and the incidence peak of postpartum flares was about 6 weeks postpartum. A total of 98% (145/148) of postpartum flares occurred within 24 weeks postpartum. After drug cessation, the incidence rate of flares was 34.1% (44/129). Conclusion: In pregnant chronic HBV carriers, a certain proportion of hepatitis flares occurred during pregnancy and postpartum regardless of whether NA intervention was used, and the incidence of postpartum flares (44.6%) was significantly higher than that (12.8%) of during pregnancy. The flare incidence peaked at approximately 6 weeks postpartum, which may be the time period suitable for treatment. Since 98% of postpartum flares occurred within 24 weeks postpartum, the follow-up after drug cessation should be at least 24 weeks postpartum.

Study on the Retreatment, Outcome, and Potential Predictors of Recurrence in Patients With Recurrence of Hepatitis B After Functional Cure.

Background: Studies about the retreatment and predictors for patients with hepatitis B recurrence after functional cure are rare. This study aimed to evaluate the effect of retreatment, outcome, and potential predictors of recurrence in patients with recurrence after functional cure. Methods: A long-term follow-up was conducted with 32 cumulatively obtained patients who relapsed after cessation of pegylated interferon (Peg-IFN)-based antiviral treatment. The decision of whether to treatment or which therapeutic method to use [Peg-IFN or nucleos(t)ide analogs (NAs)] was based on the patient's preferences and wishes. The rate of achieving functional cure and the clinical outcomes of different therapeutic methods were analyzed. Hepatitis B surface antibody (anti-HBs) and hepatitis B core antibody (anti-HBc) levels were detected in patients with blood samples during follow-up to evaluate the predictive ability of recurrence. Results: The follow-up time of 32 recurrence cases was 42-532 weeks after recurrence (median 226 weeks). In the 20 patients who received retreatment (15 received Peg-IFN and 5 received NAs only), the rate of functional cure was 65.0% (13/20); it was 86.7% (13/15) in the patients retreated with Peg-IFN. Three cases experienced recurrence again. Five patients received NA treatment, and no functional cure was achieved. No drug intervention was administered for 12 patients, 2 of them with hepatitis B virus (HBV) DNA spontaneous clearance, and one patient achieved spontaneous hepatitis B surface antigen (HBsAg) clearance during follow-up. Patients who relapsed after functional cure with Peg-IFN treatment did not have liver cirrhosis or hepatocellular carcinoma during the follow-up, regardless of whether they received retreatment. Anti-HBs and anti-HBc levels at the end of therapy were predictors of recurrence (p < 0.001, p = 0.023). The value of combining the above two indicators in predicting recurrence was further improved, the areas under the receiver operating characteristic curves were 0.833, at combining predictors >-0.386, the predictive sensitivity and specificity for recurrence were 86.67% and 90.62%. Conclusion: The functional cure rate was above 80% for patients with recurrence treated by Peg-IFN. During the follow-up, liver cirrhosis and hepatocellular carcinoma were not observed in all recurrence cases. High levels of anti-HBs and anti-HBc at the time of drug discontinuation are less likely to relapse.

Guanine Analogue-Based Assemblies: Construction and Luminescence Functions.

As one of the natural nucleobases, guanine has attracted increasing interest in molecular self-assembly science because of its abundant interaction sites and high electron cloud density. Guanines, guanine derivatives, and guanine-rich DNA sequence are able to self-assemble into versatile aggregate structures by the means of hydrogen bonds and π-π, ion-dipole, solvophobic, and electrostatic interactions. Recent advances have shown that many guanine analogue-based (G-based) luminescent aggregates exhibit promising applications for fluorescent and chemiluminescent sensing and circularly polarized luminescence (CPL). This perspective summarizes the state-of-art strategies for constructing G-based assemblies and presents representative examples for luminescence functions. Finally, the inspirations are provided for exploiting unique G-based systems and luminescent G-based assemblies.

Feedback-controlled topological reconfiguration of molecular assemblies for programming supramolecular structures.

In biology, nonequilibrium assembly is characterized by fuel-driven switching between associating and nonassociating states of biomolecules. This dynamic assembly model has been used routinely to describe the nonequilibrium processes in synthetic systems. Here, we present a G-quartet-based nonequilibrium system based on fuel-driven co-assembly of guanosine 5'-monophosphate disodium salt hydrate and urease. Addition of lanthanum(III) ions to the system caused macroscopic dynamic switching between precipitates and hydrogels. Interestingly, combined analyses of the nonequilibrium systems demonstrated that molecules could switch between two distinct associating states without undergoing a nonassociating state. This finding suggested a nonequilibrium assembly mechanism of topological reconfiguration of molecular assemblies. We detailed quantitatively the nonequilibrium assembly mechanism to precisely control the phase behaviors of the active materials; thus, we were able to use the materials for transient-gel-templated polymerization and transient circuit connection. This work presents a new nonequilibrium system with unusual phase behaviors, and the resultant active hydrogels hold promise in applications such as fluid confinements and transient electronics.

Clinical Features and T Cell Immune Characteristics of Postpartum Hepatitis Flare in Pregnant Women With HBeAg-Positive Chronic HBV Infection.

Background: The extent of the increase in postpartum alanine transaminase (ALT) varies significantly among pregnant women in the immune tolerance stage of nucleoside analogue (NA) intervention, so this study is an attempt to analyze the clinical features of patients with and without postpartum hepatitis flare and preliminarily explore the differences in their immune functions. Methods: Pregnant women with a gestational age of 24-28 w and in the immune tolerance stage of NA intervention for hepatitis B virus (HBV) infection were included and divided into a hepatitis group (Group 1) and a nonhepatitis group (Group 2) according to the ALT level at 6-12 w after childbirth. The clinical features were analyzed, and the phenotypes, functions, and cytokines of clusters of differentiation CD8+ T cells in the two groups of patients were detected using flow cytometry before and after childbirth. Results: A total of 15 patients with postpartum hepatitis flare were enrolled in Group 1, and 10 matched patients were selected as controls for Group 2. Compared with the individuals in Group 2, the postpartum clinical features in Group 1 included a remarkable elevation of the ALT level on the basis of a relatively low HBV DNA level, usually accompanied by a decline in hepatitis B virus surface antigen levels as well as HBeAg levels. In addition, CD8+ T cell activation was enhanced after childbirth in Group 1. In particular, there was a notable difference in the activation of TEMRA subsets, and the frequency of CD8+ T cells expressing perforin and granzyme B increased. Conclusion: The changes in the immune characteristics of CD8+ T cells may play a certain role in breaking down immune tolerance in patients with postpartum hepatitis flare, and the indexes related to activating and killing functions may help to indicate the population with hepatitis flare after childbirth.

Respiratory failure as the prominent manifestation of entecavir-associated mitochondrial myopathy: a case report.

BACKGROUND: Mitochondrial myopathy caused by the long-term use of nucleos(t)ide analogue in patients with chronic hepatitis B (CHB) is mostly characterized by myasthenia and myalgia. Cases with respiratory failure as the prominent manifestation and multisystem symptoms have not been reported. CASE REPORT: We report a case of mitochondrial myopathy associated with the long-term use of entecavir for CHB. The patient was a 54-year-old male who was treated with entecavir for 9 years. During the treatment, hepatitis B virus (HBV) DNA was negative and liver function was normal. However, generalized fatigue, poor appetite, dysosmia and other discomforts gradually presented starting at the 5th year of treatment, and respiratory failure was the prominent manifestation in the later stage of disease progression. The diagnosis was based on histopathology examination. The dysosmia, hypoxemia and digestive tract symptoms were gradually improved after withdrawal of entecavir. DISCUSSION: Mitochondrial myopathy is a rare side effect of entecavir and can be diagnosed by muscle biopsy. Although the incidence is extremely low, but the severe cases can lead to respiratory failure. We should receive adequate attention in clinical practice.

New focus of the cloud point/Krafft point of nonionic/cationic surfactants as thermochromic materials for smart windows.

A nonionic poly(oxyethylene) monoalkyl ether (C12(EO)6) and a cationic hexadecylpyridinium bromide (HPB) were used to achieve warm/cool transparency transition switchability, depending on the decrease in the hydration of the EO-headgroup of C12(EO)6 above the cloud point (Tc) and the crystallization of HPB below the Krafft point (Tk). The liquid state shows the advantage of being free-flowing, frost-resistance, flexible-adjustment and solar-energy-storing-capability due to the moisture-rich characteristics, while the hydrogel state exhibits free-standing properties.

Polymorphic transient glycolipid assemblies with tunable lifespan and cargo release.

HYPOTHESIS: In living systems, dynamic processes like dissipative assembly, polymorph formation, and destabilization of hydrophobic domains play an indispensable role in the biochemical processes. Adaptation of biological self-assembly processes to an amphiphilic molecule leads to the fabrication of intelligent biomaterials with life-like behavior. EXPERIMENTS: An amphiphilic glycolipid molecule was engineered into various dissipative assemblies (vesicles and supramolecular nanotube-composed hydrogels) by using two activation steps, including heating-cooling and shear force in method-1 or boric acid/glycolipid complexation and shear force in method-2. The influence of number of activation steps on vesicle to nanotube phase transitions and activation method on the properties of hydrogels were investigated, where the morphological transformations and destabilization of hydrophobic domains resulted from a bilayer to a higher-order crystal structure. FINDINGS: Hydrophobic and hydrophilic cargos encapsulated in the dissipative assemblies (vesicles and injectable hydrogels) can be released in a controlled manner via changing the activation method. The reported adaptive materials engineered by dual activation steps are promising self-assembled systems for programmed release of loaded cargos at a tunable rate.

Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions.

UCH37, also known as UCHL5, is a highly conserved deubiquitinating enzyme (DUB) that associates with the 26S proteasome. Recently, it was reported that UCH37 activity is stimulated by branched ubiquitin (Ub) chain architectures. To understand how UCH37 achieves its unique debranching specificity, we performed biochemical and Nuclear Magnetic Resonance (NMR) structural analyses and found that UCH37 is activated by contacts with the hydrophobic patches of both distal Ubs that emanate from a branched Ub. In addition, RPN13, which recruits UCH37 to the proteasome, further enhances branched-chain specificity by restricting linear Ub chains from having access to the UCH37 active site. In cultured human cells under conditions of proteolytic stress, we show that substrate clearance by the proteasome is promoted by both binding and deubiquitination of branched polyubiquitin by UCH37. Proteasomes containing UCH37(C88A), which is catalytically inactive, aberrantly retain polyubiquitinated species as well as the RAD23B substrate shuttle factor, suggesting a defect in recycling of the proteasome for the next round of substrate processing. These findings provide a foundation to understand how proteasome degradation of substrates modified by a unique Ub chain architecture is aided by a DUB.

Pegylated Interferon Treatment for the Effective Clearance of Hepatitis B Surface Antigen in Inactive HBsAg Carriers: A Meta-Analysis.

Background: Expanding antiviral therapy to benefit more populations and optimizing treatment to improve prognoses are two main objectives in current guidelines on antiviral therapy. However, the guidelines do not recommend antiviral therapy for inactive hepatitis B surface antigen (HBsAg) carriers (IHCs). Recent studies have shown that antiviral therapy is effective with good treatment outcomes in IHC populations. We conducted a systematic review and meta-analysis of HBsAg clearance and conversion in IHCs. Methods: We searched PubMed, Embase, Medline, and Web of Science to retrieve articles on HBsAg clearance in IHCs published between January 2000 and August 2021. Data were collected and analysed using the random-effects model for meta-analysis. Results: A total of 1029 IHCs from 11 studies were included in this analysis. The overall HBsAg clearance rate was 47% (95% confidence interval (CI): 31% - 64%), with a conversion rate of 26% (95% CI: 15% - 38%) after 48 weeks of Pegylated interferon (Peg-IFN) treatment. In the control group (including nucleos(t)ide analogue (NA) treatment or no treatment), the overall HBsAg clearance rate was only 1.54% (95% CI: 0.56% - 3.00%), which was markedly lower than that in the Peg-IFN group. Further analysis showed that a low baseline HBsAg level and long treatment duration contributed to a higher HBsAg clearance rate. Conclusion: This study showed that treatment of IHCs can be considered to achieve a clinical cure for chronic hepatitis B virus (HBV) infection. After Peg-IFN treatment, the HBsAg clearance rate was 47%, and the conversion rate was 26%, which are markedly higher than those reported by previous studies on Peg-IFN treatment in patients with chronic hepatitis B (CHB). A low baseline HBsAg level and long treatment duration were associated with HBsAg clearance in IHCs. Therefore, antiviral therapy is applicable for IHCs, a population who may be clinically cured. Systematic Review Registration: http://www.crd.york.ac.uk/PROSPERO, CRD): CRD42021259889.

Sono-Fenton Chemistry Converts Phenol and Phenyl Derivatives into Polyphenols for Engineering Surface Coatings.

We report a sono-Fenton strategy to mediate the supramolecular assembly of metal-phenolic networks (MPNs) as substrate-independent coatings using phenol and phenyl derivatives as building blocks. The assembly process is initiated from the generation of hydroxyl radicals (. OH) using high-frequency ultrasound (412 kHz), while the metal ions synergistically participate in the production of additional . OH for hydroxylation/phenolation of phenol and phenyl derivatives via the Fenton reaction and also coordinate with the phenolic compounds for film formation. The coating strategy is applicable to various phenol and phenyl derivatives and different metal ions including FeII , FeIII , CuII , and CoII . In addition, the sono-Fenton strategy allows real-time control over the assembly process by turning the high-frequency ultrasound on or off. The properties of the building blocks are maintained in the formed films. This work provides an environmentally friendly and controllable method to expand the application of phenolic coatings for surface engineering.

Functional cure for chronic hepatitis B: accessibility, durability, and prognosis.

Hepatitis B surface antigen (HBsAg) clearance is regarded as the ideal endpoint for antiviral treatment in terms of drug withdrawal safety and improvements in prognosis. However, the overall rate of HBsAg clearance is low and differs based on treatment method and course. The recent application of combined and extended treatment strategies have improved the HBsAg clearance rate, and several patients achieved HBsAg clearance in clinical treatment. In addition, the durability of and clinical outcomes after HBsAg clearance have become the focus of both researchers and clinicians. This article reviews HBsAg clearance in terms of accessibility, durability, improvements in prognosis and relevant advances.

Metal ion-triggered Pickering emulsions and foams for efficient metal ion extraction.

Emulsions and foams were constructed by using surfactant particles as stabilizers. Bis(2-ethylhexyl) phosphate, abbreviated as HDEHP, was used as both an oil in neutral form and an anionic surfactant in deprotonated form, DEHP-. In the system of HDEHP/H2O, upon adding NaOH, a portion of HDEHP was deprotonated to form DEHP- as stabilizers of O/W emulsions. After introducing some certain metal ions, the O/W emulsions were transformed to W/O Pickering emulsions due to the generation of insoluble particles by DEHP- and metal ions. In addition, DEHP- could also combine with some metal ions to produce particles absorbed at air/water interface, forming ultrastable foams. Accompanied with the formation of Pickering emulsions and foams, the extraction of metal ions from water could be realized with high removal efficiency. The extractant, HDEHP, could be effectively recycled through convenient demulsification of Pickering emulsions or destruction of foams. This work provides new ideas for the construction of particle-stabilized dispersion systems and proposes methods with potential applications in industrial wastewater treatments.

Concentrated exosomes from menstrual blood-derived stromal cells improves ovarian activity in a rat model of premature ovarian insufficiency.

BACKGROUND: Premature ovarian insufficiency (POI) is one of the major causes of infertility. We previously demonstrated that transplantation of menstrual blood-derived stromal cells (MenSCs) effectively improved ovarian function in a murine model of POI. Recent studies indicated that mesenchymal stem cell-derived exosomes were important components in tissue repair. In this study, we investigated the therapeutic effects of MenSCs-derived exosomes (MenSCs-Exos) in a rat model of POI and its mechanism in restoring ovulation. METHODS: Ovaries of 4.5-day-old Sprague Dawley rats (SD rats) were cultured in vitro to evaluate the effects of MenSCs-Exos exposure on early follicle development. Furthermore, POI in rats was induced by intraperitoneal administration of 4-vinylcyclohexene diepoxide (VCD). Forty-eight POI rats were randomly assigned to four groups, each receiving a different treatment: PBS, MenSCs, MenSCs-Exos, and Exo-free culture supernatant of MenSCs. Estrous cyclicity, ovarian morphology, follicle dynamics, serum hormones, pregnancy outcomes, and molecular changes were investigated. RESULTS: Exposure to MenSCs-Exos promoted the proliferation of granulosa cells in primordial and primary follicles in vitro and increased the expression of early follicle markers Deleted In Azoospermia Like (DAZL) and Forkhead Box L2 (FOXL2) while inhibiting follicle apoptosis. In vivo, MenSCs-Exos transplantation effectively promoted follicle development in the rat model of POI and restored the estrous cyclicity and serum sex hormone levels, followed by improving the live birth outcome. In addition, transplantation of MenSCs-Exos regulated the composition of the ovarian extracellular matrix and accelerated the recruitment of dormant follicles in the ovarian cortex and increased proliferation of granulosa cells in these follicles. CONCLUSION: MenSCs-Exos markedly promoted follicle development in vitro and in vivo and restored fertility in POI rats, suggesting a restorative effect on ovarian functions. The therapeutic effect of MenSCs-Exos transplantation was sustainable, consistent with that of MenSCs transplantation. Our results suggested that MenSCs-Exos transplantation may be a promising cell-free bioresource in the treatment of POI.