Exploring the therapeutic potential of DV-B-120 as an inhibitor of dengue virus infection.

Dengue fever, an infectious disease prevalent in subtropical and tropical regions, currently lacks effective small-molecule drugs as treatment. In this study, we used a fluorescence peptide cleavage assay to screen seven compounds to assess their inhibition of the dengue virus (DENV) NS2B-NS3 protease. DV-B-120 demonstrated superior inhibition of NS2B-NS3 protease activity and lower toxicity compared to ARDP0006. The selectivity index of DV-B-120 was higher than that of ARDP0006. In vivo assessments of the antiviral efficacy of DV-B-120 against DENV replication demonstrated delayed mortality of suckling mice treated with the compound, with 60-80% protection against life-threatening effects, compared to the outcomes of DENV-infected mice treated with saline. The lower clinical scores of DENV-infected mice treated with DV-B-120 indicated a reduction in acute-progressive illness symptoms, underscoring the potential therapeutic impact of DV-B-120. Investigations of DV-B-120's ability to restore the antiviral type I IFN response in the brain tissue of DENV-infected ICR suckling mice demonstrated its capacity to stimulate IFN and antiviral IFN-stimulated gene expression. DV-B-120 not only significantly delayed DENV-2-induced mortality and illness symptoms but also reduced viral numbers in the brain, ultimately restoring the innate antiviral response. These findings strongly suggest that DV-B-120 holds promise as a therapeutic agent against DENV infection and highlight its potential contribution in addressing the current lack of effective treatments for this infectious disease.IMPORTANCEThe prevalence of dengue virus (DENV) infection in tropical and subtropical regions is escalating due to factors like climate change and mosquito vector expansion. With over 300 million annual infections and potentially fatal outcomes, the urgent need for effective treatments is evident. While the approved Dengvaxia vaccine has variable efficacy, there are currently no antiviral drugs for DENV. This study explores seven compounds targeting the NS2B-NS3 protease, a crucial protein in DENV replication. These compounds exhibit inhibitory effects on DENV-2 NS2B-NS3, holding promise for disrupting viral replication and preventing severe manifestations. However, further research, including animal testing, is imperative to assess therapeutic efficacy and potential toxicity. Developing safe and potent treatments for DENV infection is critical in addressing the rising global health threat posed by this virus.

The value of SDC2 and Septin9 combined with serum tumor markers in early diagnosis of colorectal cancer.

OBJECTIVE: The aim of this study is to evaluate the significance of combined detection of Septin9 and syndecan-2 (SDC2) methylation markers and serum tumor markers for the early diagnosis of colorectal cancer. METHODS: A total of 116 patients diagnosed with colorectal cancer between December 2022 and February 2024 were designated as the colorectal cancer group. Additionally, 31 patients with colorectal adenoma were assigned to the adenoma group, while 44 individuals undergoing routine physical examinations were included in the control group. Concentrations of Septin9, SDC2, fecal occult blood (FOB), and four tumor markers-carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), carbohydrate antigen 125 (CA125), and carbohydrate antigen 724 (CA724)-were measured. Diagnostic performance was assessed using receiver operating characteristic (ROC) curves for Septin9, SDC2, the four tumor markers, FOB, the combination of Septin9 and SDC2, and the combined use of all seven indicators (CEA, CA19-9, CA125, CA72-4, FOB, Septin9, and SDC2). RESULTS: The colorectal cancer group exhibited the highest positive rates for Septin9, SDC2, the four tumor markers, the combined detection of Septin9 and SDC2, and the combined detection of all seven indicators, compared to both the adenoma and control groups (P < 0.05). The adenoma group also showed higher positive rates than the control group (P < 0.05). For patients with stage I-III colorectal cancer, the positive rates for the combined detection of Septin9 and SDC2 were 81.3%, 78.9%, and 90.2%, respectively, surpassing those for the combined detection of the four tumor markers (43.8%, 55.3%, and 61.0%). Additionally, the positive rates for the two-gene combination in stage III colorectal cancer were higher than those for FOB (P < 0.05). The sensitivity and area under the curve (AUC) for SDC2 were 73.3% and 0.855, respectively, exceeding the sensitivity and AUC for the combined four tumor markers, which were 60.3% and 0.734 (P < 0.05). The combined detection of the two methylated genes demonstrated a sensitivity of 86.2% and an AUC of 0.908, outperforming both FOB and the combined detection of the four tumor markers (P < 0.05). CONCLUSION: The detection of SDC2 exhibits high sensitivity for colorectal cancer, and when combined with Septin9, it significantly enhances the diagnostic accuracy for early-stage colorectal cancer, offering substantial clinical value.

Curcumin Improves Diabetic Cardiomyopathy by Inhibiting Pyroptosis through AKT/Nrf2/ARE Pathway.

This study is aimed at exploring whether curcumin can regulate the AKT pathway, promote the transfer of Nrf2 into the nucleus, and inhibit cell pyroptosis in diabetic cardiomyopathy. Diabetic rats and cardiomyocytes were treated with curcumin to study its effect on myocardial pyroptosis. Whether curcumin can promote the transfer of Nrf2 into the nucleus through AKT pathway regulation was assessed by western blotting and immunofluorescence. The Nrf2 knockout vector and ml385 were used to block the Nrf2 pathway, and the differences between the different groups in the expression of pyroptosis protein, cell activity, and incidence of apoptosis were evaluated to verify the relationship between the effect of curcumin on pyroptosis inhibition and the Nrf2 pathway. Curcumin promoted the transfer of Nrf2 into the nucleus through the AKT pathway and increased the expression of the antioxidant factors HO-1 and GCLC. These effects reduced reactive oxygen species accumulation and mitochondrial damage in diabetic myocardium and inhibited diabetes-induced pyroptosis. However, in cardiomyocytes with a blocked Nrf2 pathway, the ability of curcumin to inhibit pyroptosis was significantly reduced, and the protective effect on the cells was lost. Curcumin can reduce the accumulation of superoxide in the myocardium through AKT/Nrf2/ARE pathway activation and inhibit pyroptosis. It also has a role in diabetic cardiomyopathy treatment. This study provides new directions for evaluating the mechanism of diabetic cardiomyopathy and treating diabetic myocardium.

Balloon compression, neuroendoscopy and electrophysiological monitoring-assisted retrosigmoid approach for resection of cholesteatoma in the cerebellopontine angle-Meckel's cave: a technical description.

We report a case of cholesteatoma that caused left facial pain with facial numbness. The tumour was located in the left cerebellopontine angle (CPA) and Meckel's cave. A balloon was first placed into Meckel's cave, and then, under electrophysiological monitoring, the tumour within the CPA cistern was resected via the retrosigmoid approach. The balloon was inflated in Meckel's cave to push the tumour out of Meckel's cave, and then, the tumour was completely removed under endoscopy. The symptoms, including pain and numbness, subsided after surgery.

Simultaneous ground-state cooling of identical mechanical oscillators by Lyapunov control.

The simultaneous cooling of multiple mechanical oscillators in the cavity optomechanical system has aroused people's attention and may be applicable in the quantum information process. In this paper, a scheme to realize the simultaneous ground-state cooling of two identical mechanical oscillators is proposed, where the frequency of one of the oscillators is designed according to Lyapunov control. By this method, the dark mode can effectively couple with the bright mode so that the two identical oscillators can be simultaneously cooled to their ground state. Extending this scheme into multiple identical mechanical oscillators, we show that simultaneous cooling can also be achieved.

Simulating topological phases with atom arrays in an optical waveguide.

In this paper, we employ the atomic arrays in one-dimensional optical waveguides to simulate topological phases, where the waveguide is modeled as a one-dimensional infinitely long coupled cavity array. Under the Markov approximation, the coherent and dissipative coupling between atoms is established by eliminating waveguide modes. When the detuning between atoms and cavity fields lies in the band gap, the dynamics of the system is completely dominated by the coherent interaction. Under this condition, we designed three atomic arrays with different geometries and show that the topologically trivial and non-trivial phases of atomic arrays can be simulated. Furthermore, by introducing periodic atomic driving, the topological phase transition can be induced by adjusting the driving parameters. Finally, we investigate the effect of next-nearest neighbor interactions on topological state transfer and find that the next-nearest neighbor interactions break the degenerated bandgap state and establish a topological state transfer channel.

Force sensing in a dual-mode optomechanical system with linear-quadratic coupling and modulated photon hopping.

A weak force sensor scheme is presented in an optomechanical system, in which the two cavity modes couple to a mechanical mode with linear and quadratic coupling. Due to introducing time-dependent hopping, the linear and quadratic coupling terms coexist under the rotating-wave approximation in the interaction picture. Compared with the quantum non-demolition measurement (ignoring the quadratic optomechanical coupling), the current scheme can decrease the additional noise to a lower level. Our proposal provides a promising platform for improving the detection of a weak force.

Osimertinib successfully combats EGFR-negative glioblastoma cells by inhibiting the MAPK pathway.

Glioblastoma (GBM) patients have extremely poor prognoses, and currently no effective treatment available including surgery, radiation, and chemotherapy. MAPK-interacting kinases (MNK1/2) as the downstream of the MAPK-signaling pathway regulate protein synthesis in normal and tumor cells. Research has shown that targeting MNKs may be an effective strategy to treat GBM. In this study we investigated the antitumor activity of osimertinib, an FDA-approved epidermal growth factor receptor (EGFR) inhibitor, against patient-derived primary GBM cells. Using high-throughput screening approach, we screened the entire panel of FDA-approved drugs against primary cancer cells derived from glioblastoma patients, found that osimertinib (3 µM) suppressed the proliferation of a subset (10/22) of EGFR-negative GBM cells (>50% growth inhibition). We detected the gene expression difference between osimertinib-sensitive and -resistant cells, found that osimertinib-sensitive GBM cells displayed activated MAPK-signaling pathway. We further showed that osimertinib potently inhibited the MNK kinase activities with IC50 values of 324 nM and 48.6 nM, respectively, against MNK1 and MNK2 kinases; osimertinib (0.3-3 µM) dose-dependently suppressed the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). In GBM patient-derived xenografts mice, oral administration of osimertinib (40 mg· kg-1 ·d-1, for 18 days) significantly suppressed the tumor growth (TGI = 74.5%) and inhibited eIF4E phosphorylation in tumor cells. Given the fact that osimertinib could cross the blood-brain barrier and its toxicity was well tolerated in patients, our results suggest that osimertinib could be a new and effective drug candidate for the EGFR-negative GBM patients.

Efficacy of and risk factors for percutaneous balloon compression for trigeminal neuralgia in elderly patients.

OBJECTIVE: To investigate the efficacy and safety of percutaneous balloon compression (PBC) for the treatment of trigeminal neuralgia in elderly patients. Methods: We retrospectively analysed data of 105 elderly patients with primary trigeminal neuralgia who were over 70 years and underwent percutaneous balloon compression using anatomic positioning and imaging guidance from January 2019 to November 2019. Results: The immediate cure rate of pain in this group of patients was 97.1% (Barrow Neurological Institute (BNI) pain scores: class I and II; numbness score: class II). Postoperative keratitis was reported in 1 patient, masticatory muscle weakness and muscle atrophy in 1 patient, herpes labialis in 8 patients and lacunar infarction in 2 patients. Facial numbness and decreased sensation occurred in patients with significant pain relief. No serious complications were reported. There was no statistically significant difference in efficacy between the short compression and long compression time groups. Conclusion: PBC is a safe and effective approach to treat trigeminal neuralgia.

Generation of entangled Schrödinger cat state of two macroscopic mirrors.

We propose a scheme to generate the macroscopic entangled Schrödinger cat state of two mechanical resonators in a hybrid optomechanical system by introducing modulated photon-hopping interaction between two cavities. We show that the obtained entangled cat state possesses large average phonon number and the two base vectors of which are nearly orthogonal, thus causing the high degree of entanglement. To justify the robust of the scheme, the dissipation of the system and the noise from the environment are considered. It shows that the high fidelity between the obtained state and the target state can be achieved in the presence of dissipation and thermal noise within our parameter regions, which suggests that our state-generation proposal is feasible.

Homeostasis of Glucose and Lipid in Non-Alcoholic Fatty Liver Disease.

Industrialized society-caused dysregular human behaviors and activities such as overworking, excessive dietary intake, and sleep deprivation lead to perturbations in the metabolism and the development of metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide, affects around 30% and 25% of people in Western and Asian countries, respectively, which leads to numerous medical costs annually. Insulin resistance is the major hallmark of NAFLD and is crucial in the pathogenesis and for the progression from NAFLD to non-alcoholic steatohepatitis (NASH). Excessive dietary intake of saturated fats and carbohydrate-enriched foods contributes to both insulin resistance and NAFLD. Once NAFLD is established, insulin resistance can promote the progression to the more severe state of liver endangerment like NASH. Here, we review current and potential studies for understanding the complexity between insulin-regulated glycolytic and lipogenic homeostasis and the underlying causes of NAFLD. We discuss how disruption of the insulin signal is associated with various metabolic disorders of glucoses and lipids that constitute both the metabolic syndrome and NAFLD.

Optomechanical quadrature squeezing in the non-Markovian regime.

Squeezing of quantum fluctuation plays an important role in fundamental quantum physics and has marked influence on ultrasensitive detection. We propose a scheme to generate and enhance the squeezing of mechanical mode by exposing the optomechanical system to a non-Markovian environment. It is shown that the effective parametric resonance term of mechanical mode can be induced due to interaction with the cavity and non-Markovian reservoir, thus resulting in quadrature squeezing of the mechanical resonator; jointing the two kinds of interactions can enhance the squeezing effect. Compared with the usual Markovian regime, we can obtain stronger squeezing, and, significantly, the squeezing can approach a low asymptotic stable value.

Altered attention networks and DMN in refractory epilepsy: A resting-state functional and causal connectivity study.

PURPOSE: Epilepsy is considered a disorder of neural networks. Patients diagnosed with refractory epilepsy frequently experience attention impairments. Seizure activity in epilepsy may disturb brain networks and damage the brain function of attention. The aims of this study were to assess functional and causal connectivities of the attention networks and default mode network using resting-state functional magnetic resonance imaging (fMRI). METHOD: Resting-state fMRI data were gathered from 19 patients with refractory epilepsy (mixed localization and aetiologies) and 21 healthy people. The fMRI data were analyzed by group independent component analysis (ICA) fMRI toolbox to extract dorsal attention network (DAN), ventral attention network (VAN), and default mode network (DMN). The components of the selected networks were compared between patients and healthy controls to explore the change in functional connectivity (FC). Granger causality analysis was performed by taking the aforementioned significant brain areas as regions of interest (ROIs) to calculate autoregression coefficients of each pair of ROIs. Comparisons were done to find the significantly different causal connectivity when FC was changed between patients and healthy controls. RESULTS: In DAN, the FC values of the bilateral frontal eye field (FEF) and left intraparietal sulcus (IPS) were decreased. In VAN, the FC values of the double-side ventral prefrontal cortex (vPFC) and the temporoparietal junction (TPJ) were reduced. As for DMN, the FC values of the bilateral medial prefrontal cortices (mPFC) were decreased whereas those for the bilateral precuneus (PCUN) were increased. Granger causal connectivity values were correlated: causal influence was decreased significantly from the left IPS (in DAN) to the double side of the vPFC but remained the same for the right FEF (in DAN) to the right TPJ. The value was decreased from the left PCUN (in DMN) to the right TPJ and FEF, and the causal flow from the right PCUN to the right TPJ and bilateral vPFC was also significantly inhibited (p < 0.05). CONCLUSION: Frequent seizures in patients with refractory epilepsy may damage the cortex and disturb DAN, VAN, and DMN, leading to functional and causal connectivity alteration. In addition, epileptic activity may disrupt network interactions and further influence information communication.

A Flavone Constituent from Myoporum bontioides Induces M-Phase Cell Cycle Arrest of MCF-7 Breast Cancer Cells.

Myoporum bontioides is a traditional medicinal plant in Asia with various biological activities, including anti-inflammatory and anti-bacterial characteristics. To identify the bioactive constituents from M. bontioides, a newly-identified flavone, 3,4'-dimethoxy-3',5,7-trihydroxyflavone (compound 1), along with eight known compounds, were investigated in human MCF-7 breast cancer, SCC4 oral cancer, and THP-1 monocytic leukemia cells. Among these compounds, compound 1 exhibited the strongest antiproliferative activity with half-maximal inhibitory concentration (IC50) values ranging from 3.3 µM (MCF-7) to 8.6 µM (SCC4). Flow cytometric analysis indicated that compound 1 induced G2/M cell cycle arrest in MCF-7 cells. Mechanistic evidence suggests that the G2/M arrest could be attributable to compound 1's modulatory effects on the phosphorylation and expression of numerous key signaling effectors, including cell division cycle 2 (CDC2), CDC25C, and p53. Notably, compound 1 downregulated the expression of histone deacetylase 2 (HDAC2) and HDAC4, leading to increased histone H3 acetylation and p21 upregulation. Together, these findings suggest the translational potential of compound 1 as a breast cancer treatment.

Total Synthesis of Hispidulin and the Structural Basis for Its Inhibition of Proto-oncogene Kinase Pim-1.

A new method is applied to synthesize hispidulin, a natural flavone with a broad spectrum of biological activities. Hispidulin exhibits inhibitory activity against the oncogenic protein kinase Pim-1. Crystallographic analysis of Pim-1 bound to hispidulin reveals a binding mode distinct from that of quercetin, suggesting that the binding potency of flavonoids is determined by their hydrogen-bonding interactions with the hinge region of the kinase. Overall, this work may facilitate construction of a library of hispidulin-derived compounds for investigating the structure-activity relationship of flavone-based Pim-1 inhibitors.

Effects of CDNF on 6-OHDA-induced apoptosis in PC12 cells via modulation of Bcl-2/Bax and caspase-3 activation.

Progressive dopamine neuron degeneration in the substantia nigra pars compacta is considered the most prominent pathological characteristic of Parkinson's disease (PD). Currently, there is no cure, but only the capability to relieve the symptoms of PD. The conserved dopamine neurotrophic factor (CDNF) protects and rescues dopamine neurons in vivo. However, the molecular function of CDNF in PD remains unclear. In present study, we investigated the role and intrinsic mechanism of CDNF in preventing and reversing rat pheochromocytoma (PC12) cells from apoptosis induced by 6-hydroxydopamine (6-OHDA). We demonstrate that 6-OHDA induces cell death in PC12 cells, but that CDNF attenuates this effect in a dose-dependent manner. Further study shows that upregulation of the Bcl-2/Bax ratio and downregulation of caspase-3 activity are observed in a dose-dependent manner upon pre-treatment or post-treatment with CDNF, suggesting a pathway of regulation of apoptosis by CDNF. These data demonstrate that CDNF prevents the apoptosis of PC12 cells induced by 6-OHDA by modulating Bcl-2/Bax and caspase-3 activation.

Utilizing Industrial Sludge Ash in Brick Manufacturing and Quality Improvement.

This research demonstrates changes in the behaviors and characteristics of sintered bricks while using industrial sludge ash (ISA) and waste glass (WG) as a replacement for clay in the brick manufacturing procedure. Owing to the limited amount of available land in Taiwan, it is becoming increasingly difficult to locate suitable sites for sanitary landfills, which is a common final disposal method for ash that is produced during thermal treatment in sludge factories. To meet the urgent need for land, the final waste disposal must convert this waste into a new resource. This research investigated the feasibility of using general industrial sludge ash waste, due to its abundance and high potential as a raw material in producing bricks. The result of this study shows that the bricks made from ISA and WG under a certain mixture proportion (ISA50%/WG40%/Clay10%) had excellent industrial potentials, such as compressive strength and water absorption rate. However, owing to the wide variety of components from different sources of ISA, the mixture proportion might vary accordingly. This study also analyzed the incineration index, proportion design, and process improvement, as well as investigating the possibility of increasing the total use of sludge ash as a resource. This study shows the potentials of utilizing wastes as raw materials in industrial manufacturing procedures. Therefore, more wastes can be tested and turned into resources in the future.

Selective activation of IFNγ-ipilimumab enhances the therapeutic effect and safety of ipilimumab.

INTRODUCTION: Immune checkpoint inhibitor therapy is a highly promising strategy for clinical treatment of cancer. Among these inhibitors, ipilimumab stands out for its ability to induce cytotoxic T cell proliferation and activation by binding to CTLA-4. However, ipilimumab also gives rise to systemic immune-related adverse effects and tumor immune evasion, limiting its effectiveness. OBJECTIVES: We developed IFNγ-ipilimumab and confirmed that the addition of INF-γ does not alter the fundamental properties of ipilimumab. RESULTS: IFNγ-ipilimumab can be activated by matrix metalloproteinases, thereby promoting the IFNγ signaling pathway and enhancing the cytotoxicity of T cells. In vivo studies demonstrated that IFNγ-ipilimumab enhances the therapeutic effect of ipilimumab against colorectal cancer by increasing CD8+ and CD4+ lymphocyte infiltration into the tumor area and inducing MHC-I expression in tumor cells. Mice treated with IFNγ-ipilimumab showed higher survival rates and body weight, as well as lower CD4+ and CD8+ lymphocyte activation rates in the blood and reduced organ damage. CONCLUSION: IFNγ-ipilimumab improved the effectiveness of ipilimumab while reducing its side effects. It is likely that future immunotherapies would rely on such antibodies to activate local cancer cells or immune cells, thereby increasing the therapeutic effectiveness of cancer treatments and ensuring their safety.

Heated spermatozoa: effects on embryonic development and epigenetics.

BACKGROUND: Sperm chromatin is highly condensed and relatively resistant to chemical and physical treatments. The purpose of this study was to explore the highest temperature that sperm can tolerate and still produce live offspring. METHODS: Mouse sperm were heated in a water bath at 50, 65, 80 or 95°C for 30 min before they were microinjected into mouse oocytes. Fertilization, embryo development and 1-cell embryo karyotypes were evaluated. Epigenetic reprogramming including DNA methylation and histone H3K4-trimethylation were evaluated by immunofluorescent staining. RESULTS: The ability of mouse sperm to activate the egg after ICSI was heat sensitive; only 20% of eggs were activated by sperm that had been heated to 50°C and none was activated by sperm heated to 80°C. However, if eggs were activated artificially, mouse sperm subjected to 80°C for 30 min were able to produce live offspring, while 95°C treatment disabled sperm decondensation after ICSI. Once the heat-treated sperm nucleus had developed into a pronucleus, sperm chromatin was able to undergo normal active DNA demethylation and histone methylation. Aberrant chromosome rates increased from 16.3 to 100% when the temperature was raised from 50 to 95°C. CONCLUSIONS: Heat treatment destroys integrity of sperm chromatin in a temperature-dependent manner. Eighty degree Celsius was the highest temperature that mouse sperm could withstand and still produce live offspring.

Maternal insulin resistance causes oxidative stress and mitochondrial dysfunction in mouse oocytes.

BACKGROUND: Insulin resistance (IR) and hyperinsulinemia compromise fertility in females and are well-recognized characteristics of anovulatory women with polycystic ovary syndrome. Patients with IR and hyperinsulinemia undergoing ovarian stimulation for IVF are at increased risks of impaired oocyte developmental competence, implantation failure and pregnancy loss. However, the precise underlying mechanism remains unknown. METHODS: We investigated how IR impairs oocyte quality and early embryonic development by an insulin-resistant mouse model. Oocyte quality, fertilization and embryonic development were analyzed. Furthermore, oxidant stress products and mitochondrial function were evaluated by quantitative real-time PCR and immunofluorescence. RESULTS: An imbalance between oxidants and antioxidants revealed by increased concentrations of reactive oxygen species, and a decreased concentration of glutathione (GSH) and a decreased GSH/GSSG ratio resulted in oxidative stress (OS) and impaired mitochondrial function in germinal vesicle (GV) and metaphase II (MII) oocytes of insulin-resistant mice. MII oocytes displayed a decrease in the ATP content and the mitochondrial DNA (mtDNA) copy number. In contrast, GV oocytes were characterized by a high ATP content concomitant with increased clustering of mitochondria and a high inner mitochondrial membrane potential. GV oocytes from insulin-resistant mice showed early stage apoptosis, and fewer MII oocytes could be retrieved from these mice and were of poor quality associated with decreased fertilization and an arrest of embryo development with increased fragmentation. Abnormal spindles and misaligned chromosomes of MII oocyte were significantly increased in IR and hyperinsulinemia mice compared with the control mice. CONCLUSIONS: IR contributes to OS and disrupts mitochondrial function in mouse oocytes. This may impair the accurate transmission of mtDNA from one generation to the next. Therefore, our results suggest that OS and mitochondrial dysfunction are responsible for poor oocyte quality of insulin-resistant mice, and may provide novel targets to improve low fertility in females with IR.