Neuroelectrophysiological alteration associated with cognitive flexibility after 24 h sleep deprivation in adolescents.

The cognitive neural mechanisms by which sleep deprivation affects cognitive flexibility are poorly understood. Therefore, the study investigated the neuroelectrophysiological basis of the effect of 24 h sleep deprivation on cognitive flexibility in adolescents. 72 participants (36 females, mean age ± SD=20.46 ± 2.385 years old) participated in the study and were randomly assigned to the sleep deprivation group and control group. They were instructed to complete a task switch paradigm, during which participants' behavioral and electroencephalographic data were recorded. Behaviorally, there were significant between-group differences in accuracy. The results of event-related potential showed that the P2, N2 and P3 components had significant group effects or interaction effects. At the time-frequency level, there were statistically significant differences between the delta and theta bands. These results suggested that 24 h sleep deprivation affected problem-solving effectiveness rather than efficiency, mainly because it systematically impaired cognitive processing associated with cognitive flexibility.

A Comparative Study of the Early Postoperative Outcome of Three Intramedullary Fixation Modalities in the Treatment of Intertrochanteric Fractures of the Femur in the Elderly.

OBJECTIVES: To compare early outcomes of proximal femoral bionic nail (PFBN), Inter-TAN, proximal femoral nail antirotation (PFNA) for intertrochanteric fractures in elderly patients. METHODS: Eighty-two elderly patients with intertrochanteric femoral fractures treated at Xiangyang No. 1 People's Hospital affiliated with Hubei University of Medicine from December 2021 to 2022 were retrospectively analyzed. They were categorized into three surgical groups: PFBN (22 cases), Inter-TAN (20 cases), and PFNA (40 cases). Preoperative demographics and fracture characteristics were compared, alongside intraoperative and postoperative metrics like operative time and complication rates. RESULTS: In the PFBN group, operative time, fluoroscopy use, blood loss, and transfusion were higher, but postoperative weight-bearing, healing, and hospital stay were shorter compared to the Inter-TAN and PFNA groups (P<0.05). Inter-TAN had a significantly shorter postoperative weight-bearing time than PFNA (P<0.001). Other compared factors showed no significant differences between groups (P>0.05), including complication rates and scores at 6-month follow-up. CONCLUSIONS: PFBN, a novel surgical approach for intertrochanteric fractures in elderly patients, outperforms Inter-TAN and PFNA by accelerating early weight-bearing and hastening fracture recovery.

Cpne1 deficiency preserves sperm motility under Ca2+ channel blockade.

Calcium ions (Ca2+) play crucial roles in sperm motility and fertilization. The copine (CPNE) family comprises several Ca2+-dependent phospholipid-binding proteins. Of these, CPNE1 is extensively expressed in mammalian tissues; however, its precise role in testicular development and spermatogenesis is yet to be fully characterized. In this study, we used proteomics to analyze testicular biopsies and found that levels of CPNE1 were significantly reduced in patients with non-obstructive azoospermia (defective spermatogenesis) compared to those in patients with obstructive azoospermia (physiological spermatogenesis). In mice, CPNE1 is expressed at various stages of germ cell development and is associated with the Golgi apparatus. Ultimately, CPNE1 is expressed in the flagella of mature sperms. To further examine the role of CPNE1, we developed a Cpne1 knockout mouse model. Analysis showed that the loss of Cpne1 did not impair testicular development, spermatogenesis, or sperm morphology and motility in physiological conditions. When treated with gadolinium (III) chloride or 2-aminoethoxydiphenyl borate, known inhibitors of store-operated Ca2+ entry, Ca2+ signals and sperm motility were significantly compromised in wild-type mice; however, both mechanisms were conserved in KO mice. These results suggested that CPNE1 is dispensable for testicular development, spermatogenesis or sperm motility in physiological conditions. In addition, CPNE1 may represent a target of Ca2+ channel inhibitors and may therefore be implicated in the regulation of Ca2+ signaling and sperm motility.

Awake fiberoptic intubation of a patient with severe multiple trauma in prone position: a case report.

BACKGROUND: Fiberoptic-guided intubation is considered as "gold standard" of difficult airway management. Management of the airway in prone position in patients with severe trauma presenting with penetrating waist and hip injury poses a major challenge to the anesthesiologist. CASE PRESENTATION: A man presented with severe multiple trauma and hemorrhagic shock as a result of an industrial accident with several deformed steel bars penetrating the left lower waist and hip. It was decided to schedule an exploratory laparotomy following extracting the deformed steel bars. Successful administration of awake fiberoptic nasotracheal intubation, performed in a prone position under airway blocks and appropriate sedation, allowed for the procedure. The exploratory laparotomy revealed damage to multiple organs, which were repaired sequentially during a 7-hour surgical operation. The patient's recovery was uneventful, and he was discharged from the hospital one month after the surgery. CONCLUSIONS: Awake fiberoptic nasotracheal intubation, along with airway blocks and appropriate sedation, can be a viable option in patients with severe multiple trauma in the prone position.

YAP suppresses human T-cell leukemia virus type 1 transcription.

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 encodes Tax protein that activates transcription from viral long terminal repeats (LTR). Multiple cofactors are involved in the regulation of HTLV-1 transcription via association with Tax. Yes-associated protein (YAP), which is the key effector of Hippo pathway, is elevated and activated in ATL cells. In this study, we reported that YAP protein suppressed Tax activation of HTLV-1 5' LTR but not 3' LTR. The activation of the 5' LTR by Tax was potentiated when YAP was depleted. Moreover, overexpression of YAP repressed HTLV-1 plus-strand viral gene expression and virion production, whereas compromising YAP by RNA inference augmented the expression of HTLV-1 protein. As mechanisms of YAP-mediated viral transcription inhibition, we found that YAP interacted with Tax, and prevented the association between Tax and p300. It finally led to the inhibition of recruitment of Tax to the Tax-responsive element in the 5' LTR of HTLV-1. Taken together, our results demonstrate the negative regulatory function of YAP in Tax activation of HTLV-1 transcription. It may achieve sufficient transcriptional repression to maintain persistent infection and long-term latency of HTLV-1 in the host cells.

Repurposing of the FGFR inhibitor AZD4547 as a potent inhibitor of necroptosis by selectively targeting RIPK1.

Necroptosis is a form of regulated necrosis involved in various pathological diseases. The process of necroptosis is controlled by receptor-interacting kinase 1 (RIPK1), RIPK3, and pseudokinase mixed lineage kinase domain-like protein (MLKL), and pharmacological inhibition of these kinases has been shown to have therapeutic potentials in a variety of diseases. In this study, using drug repurposing strategy combined with high-throughput screening (HTS), we discovered that AZD4547, a previously reported FGFR inhibitor, is able to interfere with necroptosis through direct targeting of RIPK1 kinase. In both human and mouse cell models, AZD4547 blocked RIPK1-dependent necroptosis. In addition, AZD4547 rescued animals from TNF-induced lethal shock and inflammatory responses. Together, our study demonstrates that AZD4547 is a potent and selective inhibitor of RIPK1 with therapeutic potential for the treatment of inflammatory disorders that involve necroptosis.

Identification of key genes and pathways associated with gender difference in osteonecrosis of the femoral head based on bioinformatics analysis.

OBJECTIVE: To identify different key genes and pathways between males and females by studying differentially expressed genes (DEGs). METHODS: The gene expression data of GSE123568 were downloaded from GEO database, including osteonecrosis of the femoral head (ONFH) samples from 3 females and 7 males, and DEGs between different gender were identified with R software. Protein-protein interaction (PPI) network was constructed to further analyze the interactions between overlapping DEGs, and finally, GO, KEGG and gene set enrichment analysis (GSEA) were conducted for enrichment analysis. RESULTS: 131 DEGs were identified between ONFH females and ONFH males, including 76 up-regulated genes and 55 down-regulated genes. And 10 hub genes were identified in PPI network, including SLC4A1, GYPA, CXCL8, IFIT1, GBP5, IFI44, IFI44L, IFIT3, KEL and AHSP. Functional enrichment analysis revealed that these genes were mainly enriched in cGMP-PKG signaling pathway, Fatty acid degradation, Non-alcoholic fatty liver disease, Systemic lupus erythematosus, Hematopoietic cell lineage and NO-cGMP-PKG signaling. CONCLUSIONS: NO-cGMP-PKG signaling may play an important role in the occurrence and development of ONFH. SLC4A1, GYPA, CXCL8, GBP5 and AHSP may be key genes associated with gender difference in the progression of ONFH, which may be ideal targets or prognostic markers for the treatment of ONFH.

PRPF19 promotes the proliferation, migration, and inhibits autophagy in prostate cancer by suppressing SLC40A1.

Prostate cancer (PCa) is a common cancer and the leading cause of cancer-related death in men. To investigate the role of pre-mRNA processing factor 19 (PRPF19) in proliferation, migration of PCa, and evaluate the potential ability of PRPF19 as a therapeutic target. PRPF19 expression was analyzed from The Cancer Genome Atlas and GEPIA databank. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to evaluate the transcription of PRPF9 and solute carrier family 40 member 1 (SLC40A1). Immunohistochemistry (IHC) was used to test PRPF9 expression in PCa tissues. The cell viability and 5-ethynyl-2'-deoxyuridine incorporation analysis were performed to assess cell proliferation. Transwell assay was performed to investigate the migration and invasion of cancer cells. Western blot was used to measure the expression level of PRPF9, E-cadherin, Vimentin and α-smooth muscle actin (α-SMA), SLC40A1, LC3, Beclin-1 and ATG7. Immunofluorescence assay was performed to measure LC3 expression in PCa cells. The bioinformatic analysis revealed PRPF19 was highly expressed in PCa which was certified by qRT-PCR, western blot and IHC detection in PCa tissues. The proliferation of PCa cells could be promoted by PRPF19 overexpression and suppressed by PRPF19 knockdown. Moreover, the migration and invasion of PCa cells could be positively regulated by PRPF19 which promoted the expression of E-cadherin, Vimentin, and α-SMA. Furthermore, the expression of LC3, Beclin-1, and ATG7 was negatively regulated by PRPF19, indicating that PRPF19 inhibited autophagy in PCa cells. In the double knockdown of PRPF19 and SLC40A1, PRPF19 repressed the mRNA and reduced protein level of SLC40A1, and SLC40A1 antagonized effects of PRPF19 on proliferation, migration and autophagy of PCa cells. PRPF19 promoted proliferation and migration, and inhibited autophagy in PCa by attenuating SLC40A1 expression, indicating PRPF19 was a potential therapeutic target for PCa treatment.

Extracellular Vesicles Derived From Hypoxia-Treated Human Adipose Stem Cells Increase Proliferation and Angiogenic Differentiation in Human Adipose Stem Cells.

BACKGROUND: Adipose-derived stem cells (ADSCs) are crucial in cell-assisted lipotransfer (CAL). ADSC-derived exosomes could improve the survival of CAL. Almost all relevant research now ignores ADSCs in favor of studying the proangiogenic potential of extracellular vesicles (EVs) on human umbilical vein endothelial cells (HUVECs). OBJECTIVES: Given the significance of ADSCs in CAL, the authors sought to verify that EVs from ADSCs under hypoxia treatment can enhance the angiogenic potential of ADSCs. METHODS: EVs were harvested from human ADSCs (hADSCs) under normoxia and hypoxia. A Cell Counting Kit-8 (CCK-8) assay was used to measure the proliferation of hADSCs. By examining the expression of CD31, vascular endothelial growth factor receptor 2, and vascular endothelial growth factor, the pro-angiogenic differentiation potential was assessed. Moreover, a tube formation experiment was carried out to evaluate the pro-angiogenic differentiation potential. RESULTS: Hypoxic EVs showed more significant pro-proliferative and pro-angiogenic potential. Angiogenesis was more vigorous in hADSCs treated with hypoxic EVs than in those treated with nomorxic EVs. The hADSCs treated with hypoxic EVs expressed higher angiogenic markers, according to real-time polymerase chain reaction (RT-PCR) and Western blot analysis, which revealed more angiogenic marker expression in hypoxic EV-treated hADSCs. The same result was demonstrated by tube formation on Matrigel in vitro. CONCLUSIONS: Hypoxic EVs significantly increased the proliferation and angiogenic differentiation potential of hADSCs. Hypoxic EV-treated ADSCs may be beneficial to CAL and prevascularized tissue-engineered constructs.

Brain Functional Networks Involved in Different Premise Order in Conditional Reasoning: A Dynamic Causal Model Study.

In conditional reasoning, the reasoner must draw a conclusion based on a conditional or "If…, then…" proposition. Previous studies have reported that reversing the premises can effectively promote modus tollens reasoning (a form of conditional reasoning), but subsequent experimental studies have found no such effect. Therefore, to further examine this issue and reveal the cognitive mechanism of conditional reasoning, we asked two groups of healthy volunteers (traditional and inverted premise order groups) to evaluate a set of visually presented conditional tasks (modus ponens/modus tollens) under fMRI. The results indicated that the inverted condition activated more brain regions associated with working memory, including the angular gyrus (BA 39), precuneus (BA 7), inferior parietal lobe, and middle frontal gyrus. The resulting common activation map was used to define the ROIs and perform dynamic causal modeling for the effective connectivity analysis, containing the medial frontal gyrus, hippocampus, cerebellum, and middle occipital gyrus in the right hemisphere and the inferior occipital gyrus in the left hemisphere. The results of intrinsic connections in the optimal model selected by Bayesian model selection showed that the connection strength was stronger in the inverted group rather than in the traditional group, which may indicate that the reversal of the premise order promotes connectivity between brain regions. Despite the lack of a premise order effect, we did discover a neuronal separation between the inverted and traditional conditions, which lends support to the mental model theory to some extent.

Two-dimensional vector bending sensor based on a hole-assisted three-core fiber coupler.

We demonstrate a two-dimensional vector bending sensor based on a hole-assisted three-core fiber (HATCF) coupler. The sensor is built by splicing a section of HATCF between two single-mode fibers (SMFs). The resonance couplings between the center core and the two suspended cores of the HATCF occur at different wavelengths. Two completely discrete resonance dips are observed. The bending response of the proposed sensor is investigated over a 360° range. The bending curvature and direction can be identified by interrogating the wavelengths of the two resonance dips, and a maximum curvature sensitivity of -50.62 nm/m-1 is achieved at 0° direction. Moreover temperature sensitivity of the sensor is less than -34.9 pm/°C.

CHMFL-26 is a highly potent irreversible HER2 inhibitor for use in the treatment of HER2-positive and HER2-mutant cancers.

Oncogene HER2 is amplified in 20%-25% of human breast cancers and 6.1%-23.0% of gastric cancers, and HER2-directed therapy significantly improves the outcome for patients with HER2-positive cancers. However, drug resistance is still a clinical challenge due to primary or acquired mutations and drug-induced negative regulatory feedback. In this study, we discovered a potent irreversible HER2 kinase inhibitor, CHMFL-26, which covalently targeted cysteine 805 of HER2 and effectively overcame the drug resistance caused by HER2 V777L, HER2 L755S, HER2 exon 20 insertions, and p95-HER2 truncation mutations. CHMFL-26 displayed potent antiproliferation efficacy against HER2-amplified and mutant cells through constant HER2-mediated signaling pathway inhibition and apoptosis induction. In addition, CHMFL-26 suppressed tumor growth in a dose-dependent manner in xenograft mouse models. Together, these results suggest that CHMFL-26 may be a potential novel anti-HER2 agent for overcoming drug resistance in HER2-positive cancer therapy.

Identification of key genes and pathways associated with sex difference in osteoarthritis based on bioinformatics analysis.

OBJECTIVES: The present study aimed to identify different key genes and pathways between postmenopausal females and males by studying differentially expressed genes (DEGs). METHODS: GSE32317 and GSE55457 gene expression data were downloaded from the GEO database, and DEGs were discovered using R software to obtain overlapping DEGs. The interaction between overlapping DEGs was further analyzed by establishing the protein-protein interaction (PPI) network. Finally, GO and KEGG were used for enrichment analysis. RESULTS: 924 overlapping DEGs between postmenopausal women and men with osteoarthritis (OA) were identified, including 674 up-regulated genes and 249 down-regulated ones. And 10 hub genes were identified in the PPI network, including BMP4, KDM6A, JMJD1C, NFATC1, PRKX, SRF, ZFX, LAMTOR5, UFD1L and AMBN. The findings of the functional enrichment analysis suggested that these genes were predominantly expressed in MAPK signaling pathway as well as the Thyroid hormone signaling pathway, indicating that those two pathways may be involved in onset and disease progression of OA in postmenopausal patients. CONCLUSION: BMP4, KDM6A, JMJD1C, PRKX, ZFX and LAMTOR5 are expected to play crucial roles in disease development in postmenopausal patients and may be ideal targets or prognostic markers for the treatment of OA.

Molecular detection and subtype distribution of Blastocystis in farmed pigs in southern China.

Blastocystis is one of the most common causative agents of intestinal diseases, which can cause enteric diseases in animals and humans. However, limited data is available on the prevalence or subtypes of Blastocystis infections in farmed pigs in southern China. In this study, a total of 396 fecal samples were collected from farmed pigs in three provinces in southern China in 2016, and screened for Blastocystis by PCR amplification of the small subunit rRNA (SSU rRNA) gene fragment. One hundred and seventy (42.93%) of the examined fecal samples were detected Blastocystis-positive, and two known zoonotic subtypes ST1 and ST5 were identified, with ST5 being the predominate subtype. Moreover, gender, age and region were considered as risk factors that associated with Blastocystis infection in farmed pigs. The present study revealed the prevalence and subtypes of Blastocystis infections in farmed pigs in southern China, which provided essential data for the control of Blastocystis infections in pigs, other animals and humans in China.

First report of the prevalence and genetic characterization of Giardia duodenalis and Cryptosporidium spp. in Yunling cattle in Yunnan Province, southwestern China.

Yunling cattle is an unique cattle breed distributed in Yunnan Province, southwestern China. It is yet to know whether Yunling cattle are infected with Giardia duodenalis and Cryptosporidium spp.. The objectives of the present study were to investigate the prevalence and characterize the assemblages of G. duodenalis and species of Cryptosporidium spp. in Yunling cattle in Yunnan province. The overall prevalence of G. duodenalis and Cryptosporidium spp. were 10.49% (41/391) and 0.77% (3/391), respectively. The age was considered as the risk factor for Yunling cattle infection with G. duodenalis (χ2 = 8.082, OR = 2.56, P = 0.004). Two assemblages of G. duodenalis, assemblage A (n = 1) and assemblage E (n = 40), were identified by amplification of the ß-giardin (bg) and glutamate dehydrogenase (gdh) gene loci using the nested PCR methods. Furthermore, Cryptosporidium andersoni (n = 1) and Cryptosporidium ryanae (n = 2) were detected by nested PCR targeting the small subunit (SSU) rRNA gene. This is the first report of G. duodenalis and Cryptosporidium spp. in Yunling cattle in China, which provided baseline date for further studies of the prevalence, genetic identity, and public health potential of these parasites in Yunling cattle.

Orthogonal test design for optimizing culture medium for in vitro pollen germination of interspecific oil tea hybrids.

Oil Tea (Camellia oleifera) is an important woody edible oil plant in China. Oil Tea suffers from low rate of fruit set during production, which is related to poor pollination and fertilization. Pollen vigor is directly related to pollination and fertilization. Using the interspecific hybrid Y3 (C. grijsii × C. oleifera) as plant material, we studied the effects of sucrose, H3BO3, MgSO4, and IAA on pollen germination using an orthogonal design to determine the best culture medium. Results indicated that pollen germination rates were significantly affected by medium components and ranged from 29.13% to 56.84%. Pollen tube length was the longest in the T5 medium surpassing the control group by 489.36 µm. MgSO4 turned out to be the most important germination medium component having great effect on the pollen germination rate. The optimal culture medium to promote pollen tube growth of Oil Tea Y3 was: 1% agar, 150 g·L-1 sucrose, 0.15 g·L-1 H3BO3, 0.07 g·L-1 MgSO4, and 0.01 g·L-1 IAA. The results of this paper may provide information for foliar application of Mg and IAA, which can improve pollen tube growth of Oil Tea in practice.

Adenylate kinase 1 deficiency disrupts mouse sperm motility under conditions of energy stress†.

Mammalian spermatozoa are highly polarized cells characterized by compartmentalized cellular structures and energy metabolism. Adenylate kinase (AK), which interconverts two ADP molecules into stoichiometric amounts of ATP and AMP, plays a critical role in buffering adenine nucleotides throughout the tail to support flagellar motility. Yet the role of the major AK isoform, AK1, is still not well characterized. Here, by using a proteomic analysis of testis biopsy samples, we found that AK1 levels were significantly decreased in nonobstructive azoospermia patients. This result was further verified by immunohistochemical staining of AK1 on a tissue microarray. AK1 was found to be expressed in post-meiotic round and elongated spermatids in mouse testis and subsequent mature sperm in the epididymis. We then generated Ak1 knockout mice, which showed that AK1 deficiency did not induce any defects in testis development, spermatogenesis, or sperm morphology and motility under physiological conditions. We further investigated detergent-modeled epididymal sperm and included individual or mixed adenine nucleotides to mimic energy stress. When only ADP was available, Ak1 disruption largely compromised sperm motility, manifested as a smaller beating amplitude and higher beating frequency, which resulted in less effective forward swimming. The energy restriction/recover experiments with intact sperm further addressed this finding. Besides, decreased AK activity was observed in sperm of a male fertility disorder mouse model induced by cadmium chloride. These results cumulatively demonstrate that AK1 was dispensable for testis development, spermatogenesis, or sperm motility under physiological conditions, but was required for sperm to maintain a constant adenylate energy charge to support sperm motility under conditions of energy stress.

Metal-organic frameworks (MOFs) derived carbon-coated NiS nanoparticles anchored on graphene layers for high-performance Li-S cathode material.

Due to its high capacity (1675 mAh g-1), Li-S batteries have been considered as one of the ideal energy storage systems. The grand challenges of lithium-sulfur batteries are sulfur immobilization and improving electrical conductivity of cathode composite. The carbon-sulfur (C-S) composites and the polar materials (Ni(OH)2, TiO2, MnO2, TiS2, Co9S8, etc) integration have been proven to be two of the most effective routes to achieving good Li-S battery performance. However, each strategy has drawbacks: the C-S composites have low volume density and the polar materials are often lack of electrical conductivity. Therefore, the hybridization of carbon and polar materials shall provide synergistic effects achieving ideal sulfur cathode. Herein, a hybrid material with carbon-coated NiS nanoparticles grown on graphene sheets was synthesized through a hydrothermal reaction followed by two steps of annealing. The obtained composite has a well-balanced ratio between graphene and NiS. An optimized energy density was demonstrated in lithium-sulfur cells.

Design, synthesis and biological evaluation of novel 6-phenyl-1,3a,4,10b-tetrahydro-2H-benzo[c]thiazolo[4,5-e]azepin-2-one derivatives as potential BRD4 inhibitors.

Bromodomain-containing protein 4 (BRD4) is a key epigenetic regulator in cancer, and inhibitors targeting BRD4 exhibit great anticancer activity. By replacing the methyltriazole ring of the BRD4 inhibitor I-BET-762 with an N-methylthiazolidone heterocyclic ring, fifteen novel BRD4 inhibitors were designed and synthesized. Compound 13f had a hydrophobic acetylcyclopentanyl side chain, showing the most potent BRD4 inhibitory activity in the BRD4-BD1 inhibition assay (IC50 value of 110 nM), it also significantly suppressed the proliferation of MV-4-11 cells with high BRD4 level (IC50 value of 0.42 µM). Furthermore, the potent apoptosis-promoting and G0/G1 cycle-arresting activity of compound 13f were indicated by flow cytometry. As the downstream-protein of BRD4, c-Myc was in significantly low expression by compound 13f treatment in a dose-dependent manner. All the findings supported that this novel compound 13f provided a perspective for developing effective BRD4 inhibitors.

Discovery of novel potent GPR40 agonists containing imidazo[1,2-a]pyridine core as antidiabetic agents.

Free fatty acid receptor 1 (FFA1 or GPR40) has been studied for many years as a target for the treatment of type 2 diabetes mellitus. In order to increase potency and reduce hepatotoxicity, a series of novel compounds containing imidazo[1,2-a]pyridine scaffold as GPR40 agonist were synthesized. Compound I-14 was identified as an effective agonist as shown by the conspicuous drop in blood glucose in normal and diabetic mice. It had no risk of hepatotoxicity compared with TAK-875. Moreover, good pharmacokinetic (PK) properties of I-14 were observed (CL = 27.26 ml/h/kg, t1/2 = 5.93 h). The results indicate that I-14 could serve as a possible candidate to treat diabetes.