S-dinotefuran affects the social behavior of honeybees (Apis mellifera)and increases their risk in the colony.

The toxic effects of neonicotinoid pesticides on honeybees is a global concern, whereas little is known about the effect of stereoisomeric pesticides among honeybee social behavior. In this study, we investigated the effects of stereoisomeric dinotefuran on honeybee social behavior. We found that honeybees exhibit a preference for consuming food containing S-dinotefuran, actively engage in trophallaxis with S-dinotefuran-consuming peers, and consequently acquire higher levels of S-dinotefuran compared with R-dinotefuran. In comparison to R-dinotefuran, S-dinotefuran stimulates honeybees to elevate their body temperature, thereby attracting more peers for trophallaxis. Transcriptome analysis revealed a significant enrichment of thermogenesis pathways due to S-dinotefuran exposure. Additionally, metabolome data indicated that S-dinotefuran may enhance body temperature by promoting lipid synthesis in the lysine degradation pathway. Consequently, body temperature emerges as a key factor influencing honeybee social behavior. Our study is the first to highlight the propensity of S-dinotefuran to raise honeybee body temperature, which prompts honeybee to preferentially engage in trophallaxis with peers exhibiting higher body temperatures. This preference may lead honeybees to collect more dinotefuran-contaminated food in the wild, significantly accelerating dinotefuran transmission within a population. Proactive trophallaxis further amplifies the risk of neonicotinoid pesticide transmission within a population, making honeybees that have consumed S-dinotefuran particularly favored within their colonies. These findings may contribute to our understanding of the higher risk associated with neonicotinoid use compared with other pesticides.

Correction: Imamichi et al. Extracellular Release of HMGB1 as an Early Potential Biomarker for the Therapeutic Response in a Xenograft Model of Boron Neutron Capture Therapy. Biology 2022, 11, 420.

In the original publication [...].

Emerging biomolecules for practical theranostics of liver hepatocellular carcinoma.

Most cases of hepatocellular carcinoma (HCC) are able to be diagnosed through regular surveillance in an identifiable patient population with chronic hepatitis B or cirrhosis. Nevertheless, 50% of global cases might present incidentally owing to symptomatic advanced-stage HCC after worsening of liver dysfunction. A systematic search based on PUBMED was performed to identify relevant outcomes, covering newer surveillance modalities including secretory proteins, DNA methylation, miRNAs, and genome sequencing analysis which proposed molecular expression signatures as ideal tools in the early-stage HCC detection. In the face of low accuracy without harmonization on the analytical approaches and data interpretation for liquid biopsy, a more accurate incidence of HCC will be unveiled by using deep machine learning system and multiplex immunohistochemistry analysis. A combination of molecular-secretory biomarkers, high-definition imaging and bedside clinical indexes in a surveillance setting offers a comprehensive range of HCC potential indicators. In addition, the sequential use of numerous lines of systemic anti-HCC therapies will simultaneously benefit more patients in survival. This review provides an overview on the most recent developments in HCC theranostic platform.

Linking glucose signaling to nitrogen utilization by the OsHXK7-ARE4 complex in rice.

How reciprocal regulation of carbon and nitrogen metabolism works is a long-standing question. In plants, glucose and nitrate are proposed to act as signaling molecules, regulating carbon and nitrogen metabolism via largely unknown mechanisms. Here, we show that the MYB-related transcription factor ARE4 coordinates glucose signaling and nitrogen utilization in rice. ARE4 is retained in the cytosol in complexing with the glucose sensor OsHXK7. Upon sensing a glucose signal, ARE4 is released, is translocated into the nucleus, and activates the expression of a subset of high-affinity nitrate transporter genes, thereby boosting nitrate uptake and accumulation. This regulatory scheme displays a diurnal pattern in response to circadian changes of soluble sugars. The are4 mutations compromise in nitrate utilization and plant growth, whereas overexpression of ARE4 increases grain size. We propose that the OsHXK7-ARE4 complex links glucose to the transcriptional regulation of nitrogen utilization, thereby coordinating carbon and nitrogen metabolism.

Proteomic Characterization of SAS Cell-Derived Extracellular Vesicles in Relation to Both BPA and Neutron Irradiation Doses.

Boron neutron capture therapy (BNCT) is a selective radiotherapy based on nuclear reaction that occurs when 10B atoms accumulated in cancer cells are irradiated by thermal neutrons, triggering a nuclear fission response leading to cell death. Despite its growing importance in cancer treatment, molecular characterization of its effects is still lacking. In this context, proteomics investigation can be useful to study BNCT effect and identify potential biomarkers. Hence, we performed proteomic analysis with nanoLC-MS/MS (liquid chromatography coupled to tandem mass spectrometry) on extracellular vesicles (EVs) isolated from SAS cultures treated or not with 10B-boronophenylalanine (BPA) and different doses of neutron irradiation, to study the cellular response related to both boron administration and neutrons action. Despite the interference of fetal bovine serum in the medium, we were able to stratify BPA- and BPA+ conditions and to identify EVs-derived proteins characterizing pathways potentially related to a BNCT effect such as apoptosis, DNA repair and inflammatory response. In particular, KLF11, SERPINA1 and SERPINF2 were up-regulated in BPA+, while POLE and SERPINC1 were up-regulated in BPA-. These results provide the first proteomic investigation of EVs treated with BNCT in different conditions and highlight the potentiality of proteomics for improving biomarkers identification and mechanisms understanding of BNCT.

EEG microstate changes during hyperbaric oxygen therapy in patients with chronic disorders of consciousness.

Hyperbaric oxygen (HBO) therapy is an effective treatment for patients with disorders of consciousness (DOC). In this study, real-time electroencephalogram (EEG) recordings were obtained from patients with DOC during HBO therapy. EEG microstate indicators including mean microstate duration (MMD), ratio of total time covered (RTT), global explained variance (GEV), transition probability, mean occurrence, and mean global field power (GFP) were compared before and during HBO therapy. The results showed that the duration of microstate C in all patients with DOC increased after 20 min of HBO therapy (p < 0.05). Further statistical analysis found that the duration of microstate C was longer in the higher CRS-R group (≥8, 17 cases) than in the lower group (<8, 24 cases) during HBO treatment. In the higher CRS-R group, the transition probabilities from microstate A to microstate C and from microstate C to microstate A also increased significantly compared with the probability before treatment (p < 0.05). Microstate C is generally considered to be related to a salience network; an increase in the transition probability between microstate A and microstate C indicates increased information exchange between the auditory network and the salience network. The results of this study show that HBO therapy has a specific activating effect on attention and cognitive control in patients and causes increased activity in the primary sensory cortex (temporal lobe and occipital lobe). This study demonstrates that real-time EEG detection and analysis during HBO is a clinically feasible method for assessing brain function in patients with DOC. During HBO therapy, some EEG microstate indicators show significant changes related to the state of consciousness in patients with chronic DOC. This will be complementary to important electrophysiological indicators for assessing consciousness and may also provide an objective foundation for the precise treatment of patients with DOC.

Environmental Hormone Effects and Bioaccumulation of Propiconazole and Difenoconazole in Procypris merus.

Studying the bioaccumulation behavior and toxicity of triazole fungicides is a crucial part of comprehensively evaluating the environmental fate and aquatic toxicity.The current research aimed to reveal the toxic effects of propiconazole and difenoconazole on fish through acute toxicity test, bioaccumulation test and oxidase system activity determination. Here, the propiconazole and difenoconazole concentrations were 11.3 mg/L and 31.2 mg/L for LC50-96 h, both having low toxicity. LC-MS/MS was used to determine the propiconazole and difenoconazole concentrations in five organs (muscle, gill, liver, intestine, and kidney) of Procypris meru. The findings indicate that the bioconcentration coefficients of propiconazole and difenoconazole in grass flower carp were 0.66-27.08 and 2.43-22.72, which belonged to medium enrichment pesticides. The bioconcentration coefficients decreased with the increase of exposure concentration. The two fungicides could induce oxidative stress in fish liver, and the activities of three antioxidant enzymes were inhibited in varying degrees (p < 0.05). The results showed that the content of T3 increased, and T4 decreased when exposed to one-tenth LC50 for 7 days. This study shows that triazole pesticides have bioaccumulation risks on aquatic organisms and clear environmental hormonal effects.

Radiosensitization to γ-Ray by Functional Inhibition of APOBEC3G.

The radiosensitization of tumor cells is one of the promising approaches for enhancing radiation damage to cancer cells and limiting radiation effects on normal tissue. In this study, we performed a comprehensive screening of radiosensitization targets in human lung cancer cell line A549 using an shRNA library and identified apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G: A3G) as a candidate target. APOBEC3G is an innate restriction factor that inhibits HIV-1 infection as a cytidine deaminase. APOBEC3G knockdown with siRNA showed an increased radiosensitivity in several cancer cell lines, including pancreatic cancer MIAPaCa2 cells and lung cancer A549 cells. Cell cycle analysis revealed that APOBEC3G knockdown increased S-phase arrest in MIAPaCa2 and G2/M arrest in A549 cells after γ-irradiation. DNA double-strand break marker γH2AX level was increased in APOBEC3G-knocked-down MIAPaCa2 cells after γ-irradiation. Using a xenograft model of A549 in mice, enhanced radiosensitivity by a combination of X-ray irradiation and APOBEC3G knockdown was observed. These results suggest that the functional inhibition of APOBEC3G sensitizes cancer cells to radiation by attenuating the activation of the DNA repair pathway, suggesting that APOBEC3G could be useful as a target for the radiosensitization of cancer therapy.

Arg-Gly-Asp peptide functionalized poly-amino acid/ poly (p-benzamide) copolymer with enhanced mechanical properties and osteogenicity.

Poly-amino acid (PAA) is a promising biomaterial in biomedical engineering due to its similar amide bond structure to collagen and excellent biocompatibility, but the lack of osteogenic activity and inferior mechanical strength limit its long-term application in orthopedics. In this study, a poly-amino acid/poly (p-benzamide) (PAA-PBA) copolymer with high mechanical strength was designed and fabricated by the method of solution polymerization. The chain structures, thermal properties and mechanical properties of these polymers were evaluated and results showed that PBA greatly promoted the mechanical properties of PAA, and the copolymer performed the maximum mechanical strengths with compressive strength, bending strength and tensile strength of 123 MPa, 107 MPa and, 95 MPa, respectively. To increase the bioactivity of surface, a bioactive coating that consists of poly-(dopamine) (PDA) nanolayers and tripeptide Arginine-Glycine-Aspartic acid (RGD) on sulfonated PAA-PBA copolymer was created. A porous structure appeared on the surface after modification, the surface roughness and hydrophilicity of copolymer has been improved obviously after introducing PDA and RGD peptide coating. The in vitro bioactivity evaluation demonstrated that the RGD-functionalized sample showed a significantly improved ability to promote bone apatite mineralization, cell adhesion, proliferation and osteogenic differentiation. In a word, such a strategy of material synthesis and surface modification method shows a great potential for broadening the use of PAA in the application of load-bearing bone substitute biomaterials.

A Predictive Model for Prognosis and Therapeutic Response in Hepatocellular Carcinoma Based on a Panel of Three MED8-Related Immunomodulators.

The current tumor-node-metastasis (TNM) system is limited in predicting the survival and guiding the treatment of hepatocellular carcinoma (HCC) patients since the TNM system only focuses on the anatomical factors, regardless of the intratumoral molecule heterogeneity. Besides, the landscape of intratumoral immune genes has emerged as a prognostic indicator. The mediator complex subunit 8 (MED8) is a major polymerase regulator and has been described as an oncogene in renal cell carcinoma, but its pathophysiological significance of HCC and its contribution to the prognosis of HCC remain unclear. Here, we aimed to discuss the expression profile and clinical correlation of MED8 in HCC and construct a predictive model based on MED8-related immunomodulators as a supplement to the TNM system. According to our analyses, MED8 was overexpressed in HCC tissues and increased expression of MED8 was an indicator of poor outcome in HCC. The knockdown of MED8 weakened the proliferation, colony forming, and migration of HepG2 and Huh7 cells. Subsequently, a predictive model was identified based on a panel of three MED8-related immunomodulators using The Cancer Genome Atlas (TCGA) database and further validated in International Cancer Genome Consortium (ICGC) database. The combination of the predictive model and the TNM system could improve the performance in predicting the survival of HCC patients. High-risk patients had poor overall survival in TCGA and ICGC databases, as well as in subgroup analysis with early clinicopathology classification. It was also found that high-risk patients had a higher probability of recurrence in TCGA cohort. Furthermore, low-risk score indicated a better response to immunotherapy and drug therapy. This predictive model can be served as a supplement to the TNM system and may have implications in prognosis stratification and therapeutic guidance for HCC.

Nitric oxide negatively regulates gibberellin signaling to coordinate growth and salt tolerance in Arabidopsis.

In response to dynamically altered environments, plants must finely coordinate the balance between growth and stress responses for their survival. However, the underpinning regulatory mechanisms remain largely elusive. The phytohormone gibberellin promotes growth via a derepression mechanism by proteasomal degradation of the DELLA transcription repressors. Conversely, the stress-induced burst of nitric oxide (NO) enhances stress tolerance, largely relying on NO-mediated S-nitrosylation, a redox-based posttranslational modification. Here, we show that S-nitrosylation of Cys-374 in the Arabidopsis RGA protein, a key member of DELLAs, inhibits its interaction with the F-box protein SLY1, thereby preventing its proteasomal degradation under salinity condition. The accumulation of RGA consequently retards growth but enhances salt tolerance. We propose that NO negatively regulates gibberellin signaling via S-nitrosylation of RGA to coordinate the balance of growth and stress responses when challenged by adverse environments.

Extracellular Release of HMGB1 as an Early Potential Biomarker for the Therapeutic Response in a Xenograft Model of Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a non-invasive therapeutic technique for treating malignant tumors, however, methods to evaluate its therapeutic efficacy and adverse reactions are lacking. High mobility group box 1 (HMGB1) is an inflammatory molecule released during cell death. Therefore, we aimed to investigate HMGB1 as a biomarker for BNCT response, by examining the early responses of tumor cells to 10B-boronophenylalanine (BPA)-based BNCT in the Kyoto University Nuclear Reactor. Extracellular HMGB1 release was significantly increased in human squamous carcinoma SAS and melanoma A375 cells 24 h after neutron irradiation but not after γ-irradiation. At 3 days post-BPA-based BNCT irradiation in a SAS xenograft mouse model, plasma HMGB1 levels were higher than those in the non-irradiation control, and HMGB1 was detected in both nuclei and cytoplasm in tumor cells. Additionally, increased plasma HMGB1 levels post-BNCT irradiation were detected even when tumors decreased in size. Collectively, these results indicate that the extracellular HMGB1 release occurs at an early stage and is persistent when tumors are reduced in size; therefore, it is a potential biomarker for evaluating the therapeutic response during BNCT.

Real-time lane detection model based on non bottleneck skip residual connections and attention pyramids.

The security of car driving is of interest due to the growing number of motor vehicles and frequent occurrence of road traffic accidents, and the combination of advanced driving assistance system (ADAS) and vehicle-road cooperation can prevent more than 90% of traffic accidents. Lane detection, as a vital part of ADAS, has poor real-time performance and accuracy in multiple scenarios, such as road damage, light changes, and traffic jams. Moreover, the sparse pixels of lane lines on the road pose a tremendous challenge to the task of lane line detection. In this study, we propose a model that fuses non bottleneck skip residual connections and an improved attention pyramid (IAP) to effectively obtain contextual information about real-time scenes and improve the robustness and real-time performance of current lane detection models. The proposed model modifies the efficient residual factorized pyramid scene parsing network (ERF-PSPNet) and utilizes skip residual connections in non bottleneck-1D modules. A decoder with an IAP provides high-level feature maps with pixel-level attention. We add an auxiliary segmenter and a lane predictor side-by-side after the encoder, the former for lane prediction and the latter to assist with semantic segmentation for classification purposes, as well as to solve the gradient disappearance problem. On the CULane dataset, the F1 metric reaches 92.20% in the normal scenario, and the F1 metric of the model is higher than the F1 metrics of other existing models, such as ERFNet-HESA, ENet_LGAD, and DSB+LDCDI, in normal, crowded, night, dazzling light and no line scenarios; in addition, the mean F1 of the nine scenarios reached 74.10%, the runtime (time taken to test 100 images) of the model was 5.88 ms, and the number of parameters was 2.31M, which means that the model achieves a good trade-off between real-time performance and accuracy compared to the current best results (i.e., a running time of 13.4 ms and 0.98M parameters).

Juvenile hormone and transcriptional changes in honey bee worker larvae when exposed to sublethal concentrations of thiamethoxam.

Thiamethoxam, an insecticide with high usage and large amounts of environmental residues, has been reported to affect the pupation and survival of honey bee larvae at sublethal concentrations. The molecular mechanisms are not fully understood. In this study, we measured the response of juvenile hormone (JH) to environmental concentrations of thiamethoxam using liquid chromatography-tandem mass spectrometry (LC-MS/MS), monitored the dynamic changes in the transcription of genes encoding major JH metabolic enzymes (CYP15A1, FAMET, JHAMT and JHE) using RT-qPCR, and analysed the transcriptome changes in worker larvae under thiamethoxam stress using RNA-seq. Thiamethoxam significantly increased the levels of JH3 in honey bee larvae, but no significant changes in the transcript levels of the four major metabolic enzymes were observed. Thiamethoxam exposure resulted in 140 differentially expressed genes (DEGs). P450 CYP6AS5 was upregulated, and some ion-related, odourant-related and gustatory receptors for sugar taste genes were altered significantly. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that amino acid metabolism and protein digestion and absorption were influenced by thiamethoxam. These changes may do harm to honey bee caste differentiation, foraging behaviour related to sensory perception and nutrient levels of bee colonies. These results represent the first assessment of the effects of thiamethoxam on JH in honey bee larvae and provides a new perspective and molecular basis for the study of JH regulation and thiamethoxam toxicity to honey bees.

A newly established monoclonal antibody against ERCC1 detects major isoforms of ERCC1 in gastric cancer.

Identifying patients resistant to cisplatin treatment is expected to improve cisplatin-based chemotherapy for various types of cancers. Excision repair cross-complementing group 1 (ERCC1) is involved in several repair processes of cisplatin-induced DNA crosslinks. ERCC1 overexpression is reported as a candidate prognostic factor and considered to cause cisplatin resistance in major solid cancers. However, anti-ERCC1 antibodies capable of evaluating expression levels of ERCC1 in clinical specimens were not fully optimized. A mouse monoclonal antibody against human ERCC1 was generated in this study. The developed antibody 9D11 specifically detected isoforms of 201, 202, 203 but not 204, which lacks the exon 3 coding region. To evaluate the diagnostic usefulness of this antibody, we have focused on gastric cancer because it is one of the major cancers in Japan. When ERCC1 expression was analyzed in seventeen kinds of human gastric cancer cell lines, all the cell lines were found to express either 201, 202, and/or 203 as major isoforms of ERCC1, but not 204 by Western blotting analysis. Immunohistochemical staining showed that ERCC1 protein was exclusively detected in nuclei of the cells and a moderate level of constant positivity was observed in nuclei of vascular endothelial cells. It showed a clear staining pattern in clinical specimens of gastric cancers. Antibody 9D11 may thus be useful for estimating expression levels of ERCC1 in clinical specimens.

A Combination of GM-CSF and Released Factors from Gamma-Irradiated Tumor Cells Enhances the Differentiation of Macrophages from Bone Marrow Cells and Their Antigen-Presenting Function and Polarization to Type 1.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) promotes dendritic cell differentiation from precursors, and consequently, enhances the antigen presentation process and adaptive immune responses. With such functions, GM-CSF has been used as immunotherapy in combination with radiotherapy for cancer treatment to augment the survival and activity of immune cells. However, an immune-suppressive tumor microenvironment may cause anergy of T cells. It has also been reported that GM-CSF contributes to the development of myeloid-derived suppressor cells from the precursors. In this study, to analyze the combined effect of GM-CSF and released factors from cancer cells after gamma-ray irradiation on bone marrow cell differentiation and dynamics, we established an in vitro culture system using mouse bone marrow cells, GM-CSF, and conditioned medium from gamma ray irradiated mouse melanoma B16 cells at 24 Gy. We analyzed the gene expression changes of the bone marrow-derived cells on day 6. The results showed that GM-CSF dose-dependently enhanced the differentiation of macrophages from bone marrow cells, their antigen-presenting function and polarization to type I. The results implied the induced macrophages from the bone marrow may potentially contribute to tumor immune responses in a systemic manner when GM-CSF is boosted during photon-beam radiation therapy.

CM-supplement network model for reducing the memory consumption during multilabel image annotation.

With the rapid development of the Internet and the increasing popularity of mobile devices, the availability of digital image resources is increasing exponentially. How to rapidly and effectively retrieve and organize image information has been a hot issue that urgently must be solved. In the field of image retrieval, image auto-annotation remains a basic and challenging task. Targeting the drawbacks of the low accuracy rate and high memory resource consumption of current multilabel annotation methods, this study proposed a CM-supplement network model. This model combines the merits of cavity convolutions, Inception modules and a supplement network. The replacement of common convolutions with cavity convolutions enlarged the receptive field without increasing the number of parameters. The incorporation of Inception modules enables the model to extract image features at different scales with less memory consumption than before. The adoption of the supplement network enables the model to obtain the negative features of images. After 100 training iterations on the PASCAL VOC 2012 dataset, the proposed model achieved an overall annotation accuracy rate of 94.5%, which increased by 10.0 and 1.1 percentage points compared with the traditional convolution neural network (CNN) and double-channel CNN (DCCNN). After stabilization, this model achieved an accuracy of up to 96.4%. Moreover, the number of parameters in the DCCNN was more than 1.5 times that of the CM-supplement network. Without increasing the amount of memory resources consumed, the proposed CM-supplement network can achieve comparable or even better annotation effects than a DCCNN.

Transnitrosylation Mediated by the Non-canonical Catalase ROG1 Regulates Nitric Oxide Signaling in Plants.

The redox-based protein S-nitrosylation is a conserved mechanism modulating nitric oxide (NO) signaling and has been considered mainly as a non-enzymatic reaction. S-nitrosylation is regulated by the intracellular NO level that is tightly controlled by S-nitrosoglutathione reductase (GSNOR). However, the molecular mechanisms regulating S-nitrosylation selectivity remain elusive. Here, we characterize an Arabidopsis "repressor of" gsnor1 (rog1) mutation that specifically suppresses the gsnor1 mutant phenotype. ROG1, identical to the non-canonical catalase, CAT3, is a transnitrosylase that specifically modifies GSNOR1 at Cys-10. The transnitrosylase activity of ROG1 is regulated by a unique and highly conserved Cys-343 residue. A ROG1C343T mutant displays increased catalase but decreased transnitrosylase activities. Consistent with these results, the rog1 mutation compromises responses to NO under both normal and stress conditions. We propose that ROG1 functions as a transnitrosylase to regulate the NO-based redox signaling in plants.

Co(O)x Particles in Polymeric N-Doped Carbon Nanotube Applied for Photocatalytic H2 or Electrocatalytic O2 Evolution.

A new way for synthesizing porous composite with cobalt species and N-doped carbon nanotubes (NDCNTs) was reported here by using cobalt salts and melamine mixtures as precursor. The Co(O)x/NDCNTs exhibited good activity of electrocatalytic O2 production. Furthermore, after reduced by H2, the Co-NDCNTs showed strong absorption of visible light and high catalytic activity of H2 production, which is 598.5 µmol g-1 h-1 under the visible light (λ > 420 nm). The results suggested that supramolecular preorganization of melamine monomers may be a promising method of synthesizing two-dimensional N-doped carbon nanotube with Co particles in it. The morphologies should be beneficial for the charge transport and separation. This work can encourage further synthesize new efficient noble-metal-free photocatalysts or electrocatalysts.

Development of renal failure in PargParp-1 null and Timm23 hypomorphic mice.

Poly(ADP-ribose) glycohydrolase (Parg) is a central enzyme for poly(ADP-ribose) degradation. We established a Parg+/- mice strain by deletion of a part of exon 1 and around 0.4-kb upstream of sequences of the Parg gene. Parg-/- embryos obtained by intercrossing the Parg+/- mice died in utero between 4.5 and 9.5 days postcoitum. We examined whether poly(ADP-ribose) polymerase-1 (Parp-1) deficiency could rescue embryonic lethality of Parg-/- mice. Parg-/-Parp-1-/- mice were born viable at a reduced frequency from the expected mendelian ratio in the intercross progeny of Parg+/-Parp-1-/- mice. The results suggest a possibility that the presence of Parp-1 is responsible for the lethality of Parg-/- embryos, and Parg molecules or Parg activity degrading poly(ADP-ribose) might be important for embryogenesis. In Parg-/-Parp-1-/- mice, Parg protein was not detected in various tissues, and the protein level of Timm23, a 5'-upstream gene of Parg, was reduced compared with that in Parg+/+Parp-1-/- mice. Parg-/-Parp-1-/- mice showed retarded growth compared with Parg+/+Parp-1-/- mice, and died within 3 months of age accompanied with severe renal failure. Glomerular sclerosis, tubular dilatation, and hyaline casts in the kidney were observed in Parg-/-Parp-1-/- mice. An increase in blood urea nitrogen (p < 0.05), a marked increase of albumin level in urine (p < 0.01) and its concomitant decrease in serum (p < 0.05) were also detected in Parg-/-Parp-1-/- mice compared with the Parg+/+Parp-1-/- counterpart. The results imply that the combined Parg and Parp-1 loss with a hypomorphic state of Timm23 leads to the development of severe renal failure.