The first report of single nucleotide polymorphisms in the open reading frame of the prion-like protein gene in rabbits.

Background: Natural cases of prion disease have not been reported in rabbits, and prior attempts to identify a prion conversion agent have been unsuccessful. However, recent applications of prion seed amplifying experimental techniques have sparked renewed interest in the potential susceptibility of rabbits to prion disease infections. Among several factors related to prion disease, polymorphisms within the prion-like protein gene (PRND), a member of the prion protein family, have been reported as significantly associated with disease susceptibility in various species. Therefore, our study aimed to investigate polymorphisms in the PRND gene of rabbits and analyze their genetic characteristics. Methods: Genomic DNA was extracted from 207 rabbit samples to investigate leporine PRND polymorphisms. Subsequently, amplicon sequencing targeting the coding region of the leporine PRND gene was conducted. Additionally, linkage disequilibrium (LD) analysis was employed to assess the connection within and between loci. The impact of non-synonymous single nucleotide polymorphisms (SNPs) on the Doppel protein was evaluated using PolyPhen-2. Results: We found nine novel SNPs in the leporine PRND gene: c.18A > G, c.76G > C, c.128C > T, c.146C > T, c.315A > G, c.488G > A, c.525G > C, c.544G > A, and c.579A > G. Notably, seven of these PRND SNPs, excluding c.525G > C and c.579A > G, exhibited strong LD values exceeding 0.3. In addition, LD analysis confirmed a robust link between PRNP SNP c.234C > T and PRND SNPs at c.525G > C and c.579A > G. Furthermore, according to PolyPhen-2 and SIFT analyses, the four non-synonymous SNPs were predicted to have deleterious effects on the function or structure of the Doppel protein. However, PANTHER and Missense3D did not indicate such effects. Conclusion: In this paper, we have identified novel SNPs in the rabbit PRND gene and predicted their potential detrimental effects on protein function or structure through four non-synonymous SNPs. Additionally, we observed a genetic linkage between SNPs in the PRND and PRNP genes. These findings may provide insights into understanding the characteristics of rabbits as partially resistant species. To the best of our knowledge, this study is the first to genetically characterize PRND SNPs in rabbits.

Lagerstroemia macrocarpa extract inhibits Th2-mediated STAT6 signaling pathway in human keratinocytes.

In this study, we examined physiological functions as a key material to develop cosmeceuticals using extracts of Lagerstroemia macrocarpa Wall. Ex Kurz (L. macrocarpa). Initially, the L. macrocarpa extract was treated by different concentration and antioxidant assay (DPPH and ABTS) were performed to measure free radical scavenging ability. In the cytotoxicity experiment, the extract was treated into human epidermal keratinocytes with different concentrations to measure cytotoxicity. We found that the extract induces differentiation markers such as keratin (KRT)1, KRT2, KRT9, KRT10 in keratinocytes. Furthermore, the extract significantly induces involucrin (IVL), loricrin (LOR), claudin1 (CLDN1), and filaggrin (FLG) expression, suggesting that it may enhance skin barrier functions. Especially, the extract restored FLG expression inhibited by interleukin (IL)-4/IL-13 in in vitro atopic dermatitis-like model. Therefore, we expect L. macrocarpa extract will be an effective material to develop the therapeutic and cosmeceutical of atopic dermatitis.

Viral vector-mediated transgene delivery with novel recombinase systems for targeting neuronal populations defined by multiple features.

A comprehensive understanding of neuronal diversity and connectivity is essential for understanding the anatomical and cellular mechanisms that underlie functional contributions. With the advent of single-cell analysis, growing information regarding molecular profiles leads to the identification of more heterogeneous cell types. Therefore, the need for additional orthogonal recombinase systems is increasingly apparent, as heterogeneous tissues can be further partitioned into increasing numbers of specific cell types defined by multiple features. Critically, new recombinase systems should work together with pre-existing systems without cross-reactivity in vivo. Here, we introduce novel site-specific recombinase systems based on ΦC31 bacteriophage recombinase for labeling multiple cell types simultaneously and a novel viral strategy for versatile and robust intersectional expression of any transgene. Together, our system will help researchers specifically target different cell types with multiple features in the same animal.

The first report of polymorphisms of the prion protein gene (PRNP) in Pekin ducks (Anas platyrhynchos domestica).

Background: Prion diseases have been extensively reported in various mammalian species and are caused by a pathogenic prion protein (PrPSc), which is a misfolded version of cellular prion protein (PrPC). Notably, no cases of prion disease have been reported in birds. Single nucleotide polymorphisms (SNPs) of the prion protein gene (PRNP) that encodes PrP have been associated with susceptibility to prion diseases in several species. However, no studies on PRNP polymorphisms in domestic ducks have been reported thus far. Method: To investigate PRNP polymorphisms in domestic ducks, we isolated genomic DNA from 214 Pekin duck samples and sequenced the coding region of the Pekin duck PRNP gene. We analyzed genotype, allele, and haplotype distributions and linkage disequilibrium (LD) among the SNPs of the Pekin duck PRNP gene. In addition, we evaluated the effects of the one non-synonymous SNP on the function and structure of PrP using the PROVEAN, PANTHER, SNPs & GO, SODA, and AMYCO in silico prediction programs. Results: We found five novel SNPs, c.441 T > C, c.495 T > C, c.582A > G, c.710C > T(P237L), and c.729C > T, in the ORF region of the PRNP gene in 214 Pekin duck samples. We observed strong LD between c.441 T > C and c.582A > G (0.479), and interestingly, the link between c.495 T > C and c.729C > T was in perfect LD, with an r2 value of 1.0. In addition, we identified the five major haplotype frequencies: TTACC, CTGCC, CTACC, CCGCT, and CTATC. Furthermore, we found that the non-synonymous SNP, c.710C > T (P237L), had no detrimental effects on the function or structure of Pekin duck PrP. However, the non-synonymous SNP had deleterious effects on the aggregation propensity and solubility of Pekin duck PrP compared with wildtype Pekin duck PrP. Conclusion: To the best of our knowledge, this study is the first report on the genetic characteristics of PRNP SNPs in Pekin ducks.

Optimization of extraction condition for platycodin D from Platycodon grandiflorum root and verification of its biological activity.

Platycosides, major components of Platycodon grandiflorum (PG) extract, have been implicated in a wide range of biological effects. In particular, platycodin D (PD) is a well-known main bioactive compound of Platycosides. Despite the biological significance of PD, optimization of extract condition for PD from PG root has not been well investigated. Here, we established the optimum extraction condition as ethanol concentration of 0%, temperature of 50°C, and extraction time of 11 h to obtain PD-rich P. grandiflorum extract (PGE) by using response surface methodology (RSM) with Box-Behnken design (BBD). The 5.63 mg/g of PD was extracted from the PG root in optimum condition, and this result was close to the predicted PD content. To analyze the biological activity of PGE related to mucin production, we demonstrated the inhibitory effect of PGE on PMA-induced hyperexpression of MUC5AC as well as ERK activation, a signal mediator of MUC5AC expression. Moreover, we showed that PGE had expectorant activity in mice. These results indicated that PGE had sufficient functions as a potential mucoregulator and expectorant for treating diverse airway diseases. Additionally, we confirmed that PGE had antioxidant activity and inhibited LPS-induced proinflammatory cytokines, TNF-α, and IL-6. Taken together, PGE derived from novel optimizing conditions showed various biological effects, suggesting that PGE could be directly applied to the food industry as food material having therapeutic and preventive potential for human airway diseases.

Identification of a novel risk factor for chronic wasting disease (CWD) in elk: S100G single nucleotide polymorphism (SNP) of the prion protein gene (PRNP).

Prion diseases are fatal and malignant infectious encephalopathies induced by the pathogenic form of prion protein (PrPSc) originating from benign prion protein (PrPC). A previous study reported that the M132L single nucleotide polymorphism (SNP) of the prion protein gene (PRNP) is associated with susceptibility to chronic wasting disease (CWD) in elk. However, a recent meta-analysis integrated previous studies that did not find an association between the M132L SNP and susceptibility to CWD. Thus, there is controversy about the effect of M132L SNP on susceptibility to CWD. In the present study, we investigated novel risk factors for CWD in elk. We investigated genetic polymorphisms of the PRNP gene by amplicon sequencing and compared genotype, allele, and haplotype frequencies between CWD-positive and CWD-negative elk. In addition, we performed a linkage disequilibrium (LD) analysis by the Haploview version 4.2 program. Furthermore, we evaluated the 3D structure and electrostatic potential of elk prion protein (PrP) according to the S100G SNP using AlphaFold and the Swiss-PdbViewer 4.1 program. Finally, we analyzed the free energy change of elk PrP according to the S100G SNP using I-mutant 3.0 and CUPSAT. We identified 23 novel SNP of the elk PRNP gene in 248 elk. We found a strong association between PRNP SNP and susceptibility to CWD in elk. Among those SNP, S100G is the only non-synonymous SNP. We identified that S100G is predicted to change the electrostatic potential and free energy of elk PrP. To the best of our knowledge, this was the first report of a novel risk factor, the S100G SNP, for CWD.

A brainstem-to-mediodorsal thalamic pathway mediates sound-induced arousal from slow-wave sleep.

Auditory-induced arousal is a defense mechanism of animals against potential dangers. Although the thalamus is the neural substrate that relays sensory information to the cortex, its function is reduced during slow-wave sleep (SWS), also known as deep sleep. Despite this, animals are capable of waking up in response to external sensory stimuli, suggesting the existence of neural circuits that are involved in this response. Here, we report that kainate-class-type ionotropic glutamate receptor subunit 4 (GRIK4)-positive mediodorsal (MD) thalamic neurons act as a neural substrate for arousals from SWS. These neurons become active during arousal from SWS and their photoactivation can induce arousal from SWS. Moreover, we show that these neurons are influenced by glutamatergic neurons in the brainstem, the activity of which increases during auditory-induced arousals. These results suggest that this brainstem-MD pathway can mediate wakefulness from SWS.

Early adversity promotes binge-like eating habits by remodeling a leptin-responsive lateral hypothalamus-brainstem pathway.

Early-life trauma (ELT) is a risk factor for binge eating and obesity later in life, yet the neural circuits that underlie this association have not been addressed. Here, we show in mice that downregulation of the leptin receptor (Lepr) in the lateral hypothalamus (LH) and its effect on neural activity is crucial in causing ELT-induced binge-like eating and obesity upon high-fat diet exposure. We also found that the increased activity of Lepr-expressing LH (LHLepr) neurons encodes sustained binge-like eating in ELT mice. Inhibition of LHLepr neurons projecting to the ventrolateral periaqueductal gray normalizes these behavioral features of ELT mice. Furthermore, activation of proenkephalin-expressing ventrolateral periaqueductal gray neurons, which receive inhibitory inputs from LHLepr neurons, rescues ELT-induced maladaptive eating habits. Our results identify a circuit pathway that mediates ELT-induced maladaptive eating and may lead to the identification of novel therapeutic targets for binge eating and obesity.

Glycine max Fermented by a Novel Probiotic, Bifidobacterium animalis subsp. lactis LDTM 8102, Increases Immuno-Modulatory Function.

Many probiotic species have been used as a fermentation starter for manufacturing functional food materials. We have isolated Bifidobacterium animalis subsp. lactis LDTM 8102 from the feces of infants as a novel strain for fermentation. While Glycine max has been known to display various bioactivities including anti-oxidant, anti-skin aging, and anti-cancer effects, the immune-modulatory effect of Glycine max has not been reported. In the current study, we have discovered that the extract of Glycine max fermented with B. animalis subsp. lactis LDTM 8102 (GFB 8102), could exert immuno-modulatory properties. GFB 8102 treatment increased the production of immune-stimulatory cytokines in RAW264.7 macrophages without any noticeable cytotoxicity. Analysis of the molecular mechanism revealed that GFB 8102 could upregulate MAPK2K and MAPK signaling pathways including ERK, p38, and JNK. GFB 8102 also increased the proliferation rate of splenocytes isolated from mice. In an animal study, administration of GFB 8102 partially recovered cyclophosphamide-mediated reduction in thymus and spleen weight. Moreover, splenocytes from the GFB 8102-treated group exhibited increased TNF-α, IL-6, and IL-1ß production. Based on these findings, GFB 8102 could be a promising functional food material for enhancing immune function.

Development of a chicken interferon-induced transmembrane protein 3 (IFITM3)-specific monoclonal antibody using phage display.

Interferon-induced transmembrane protein 3 (IFITM3) has potent antiviral activity against several viruses. Recent studies have reported that the chicken IFITM3 gene also plays a pivotal role in blocking viral replication, but these studies are considerably limited due to being conducted at the RNA level only. Thus, the development of a chicken IFITM3 protein-specific antibody is needed to validate the function of IFITM3 at the protein level. Epitope prediction was performed with the immune epitope database analysis resource (IEDB-AR) program. The epitope was validated by four in silico programs, Jped4, Clustal Omega, TMpred and SOSUI. Chicken IFITM3 protein-specific monoclonal antibodies were screened by enzyme-linked immunosorbent assay through affinity between recombinant IFITM3 protein and phage-displayed candidate antibodies. Validation of the reactivity of the chicken IFITM3 protein-specific antibody to chicken tissues was carried out using western blotting. We developed a chicken IFITM3 protein-specific monoclonal antibody using phage display. The reactivity of the antibody with peripheral chicken tissues was confirmed using western blotting. To the best of our knowledge, this was the first development of a chicken IFITM3 protein-specific monoclonal antibody using phage display.

First report of a strong association between genetic polymorphisms of the prion protein gene (PRNP) and susceptibility to chronic wasting disease in sika deer (Cervus nippon).

Prion diseases are incurable neurodegenerative disorders caused by proteinase K-resistant prion protein (PrPSc ) derived from normal prion protein (PrPC ) encoded by the prion protein gene (PRNP). Although the cervid PRNP gene plays a pivotal role in the pathological mechanism of chronic wasting disease (CWD), there is no existing association analysis between susceptibility to CWD and genetic polymorphisms of the PRNP gene in sika deer. We investigated genetic polymorphisms of the PRNP gene using amplicon sequencing in sika deer. In addition, to identify a genetic susceptibility factor, we compared the genotype, allele and haplotype frequencies of the PRNP gene between CWD-positive and CWD-negative sika deer. Furthermore, to assess the effect of the genetic polymorphisms on sika deer prion protein (PrP), we performed in silico analysis using PolyPhen-2, PROVEAN and AMYCO. Finally, we analysed the tertiary structure and electrostatic potential of sika deer PrP based on single nucleotide polymorphisms (SNPs) using the SWISS-MODEL and Swiss-PdbViewer programs. We found a total of 24 SNPs of the PRNP gene, including 22 novel SNPs (10 synonymous SNPs and 12 nonsynonymous SNPs), in sika deer. Among the nonsynonymous SNPs, we found a strong association of susceptibility to CWD with c.56G > A (Ser19Asn). In addition, we found that c.56G > A (Ser19Asn), c.296A > T (His99Leu) and c.560T > A (Val187Asp) were predicted to have damaging effects on sika deer PrP. Furthermore, we observed significant alterations in the electrostatic potential of sika deer PrP by genetic polymorphisms of the 187Asp allele. To the best of our knowledge, this was the first association study between genetic polymorphisms of the PRNP gene and susceptibility to CWD in sika deer.

8-Shogaol inhibits rheumatoid arthritis through targeting TAK1.

Rheumatoid arthritis (RA) is a chronic immune-mediated disorder, mainly characterized by synovial inflammation and joint damage. If insufficiently treated, RA can lead to irreversible joint destruction and decreased life expectancy. While better understanding of the pathologies and the development of new antirheumatic drugs have improved the outcome of individuals with RA, many patients still cannot achieve remission and experience progressive disability. Fibroblast-like synoviocytes (FLS) have gained attention due to its pivotal role in RA pathogenesis and thus targeting FLS has been suggested as an attractive therapeutic strategy. To identify candidate molecules with strong inhibitory activity against FLS inflammation, we tested the effect of 315 natural extracts against IL-17-mediated IL-6 production. Zingiber officinale was found as the top hit and further analysis on the active compound responsible led to the discovery of 8-shogaol as a potent molecule against synovitis. 8-Shogaol displayed significant inhibitory effects against TNF-α-, IL-1ß-, and IL-17-mediated inflammation and migration in RA patient-derived FLS (RA-FLS) and 3D synovial culture system. 8-Shogaol selectively and directly inhibited TAK1 activity and subsequently suppressed IKK, Akt, and MAPK signaling pathways. Moreover, treatment with 8-shogaol reduced paw thickness and improved walking performance in the adjuvant-induced arthritic (AIA) rat model. 8-Shogaol also reversed pathologies of joint structure in AIA rats and decreased inflammatory biomarkers in the joints. Collectively, we report a novel natural compound that inhibits RA through reversing pathologies of the inflamed synovium via targeting TAK1.

Absence of proteinase K-resistant PrP in Korean Holstein cattle carrying potential bovine spongiform encephalopathy-related E211K somatic mutation.

Bovine spongiform encephalopathy (BSE) is a kind of prion disease caused by proteinase K-resistant prion protein (PrPSc ) in cattle. Although BSE has been reported worldwide, BSE-infected cases have never been reported in Korea. In a previous study, we identified BSE-related somatic mutation E211K in 3 Korean Holstein cattle. In Korea, the BSE surveillance system has been established. However, several genetic factors have not been controlled simultaneously thus far. In the present study, we performed enhanced surveillance of prion disease-related factors in Korean cattle, including Holstein cattle and Hanwoo (Korean native cattle), which is widely raised for meat. We investigated the germline mutation E211K at codon 211 of the PRNP gene and analysed genotype, allele and haplotype frequencies of the 23- and 12-bp insertion/deletion polymorphisms of the PRNP gene using direct DNA sequencing. In addition, we investigated linkage disequilibrium (LD) and compared haplotype distributions of polymorphisms among cattle breeds. Furthermore, we carried out BSE diagnosis in the medulla oblongata (MO) of Korean cattle including 3 Korean Holstein cattle carrying somatic mutation E211K using Western blotting analysis. We did not find the E211K mutation in the PRNP gene in any of the Korean cattle and found significantly different genotype, allele and haplotype distributions of the 23- and 12-bp insertion/deletion polymorphisms of the PRNP gene in male Holstein compared with male Hanwoo, female Hanwoo and total Hanwoo. In addition, only male Holstein showed weak LD between 23- and 12-bp insertion/deletion polymorphisms. Furthermore, the PrPSc bands were not detected in all Korean cattle tested. To the best of our knowledge, the enhanced surveillance system of BSE was conducted for the first time in Korean cattle.

Polymorphisms of the prion-related protein gene are strongly associated with cervids' susceptibility to chronic wasting disease.

BACKGROUND: Chronic wasting disease (CWD) is a cervid prion disease that is caused by abnormal prion protein (PrPSc ). Recent studies have reported that prion family genes showed a strong association with the susceptibility of several types of prion diseases. To date, an association study of the prion-related protein gene (PRNT) has not been performed in any type of cervid prion disease. METHODS: In the present study, we investigated PRNT polymorphisms in large deer, including 235 elk, 257 red deer and 150 sika deer. We compared genotype, allele and haplotype frequencies of PRNT polymorphisms between CWD-negative animals and CWD-positive animals to find an association of PRNT polymorphisms with the susceptibility of CWD. RESULTS: We found a total of five novel single nucleotide polymorphisms (SNPs) in the cervid PRNT gene. Interestingly, we observed significantly different distributions of genotypes and allele frequencies of three PRNT SNPs, including c.108C>T, c.159+30C>T and c.159+32A>C, between CWD-negative and CWD-positive red deer. In addition, significant differences of two haplotype frequencies in red deer were found between the CWD-negative and CWD-positive groups. However, the association identified in the red deer was not found in elk and sika deer. CONCLUSION: To the best of our knowledge, this report is the first to describe the strong association of PRNT SNPs with the susceptibility of CWD.

Regulatory Single Nucleotide Polymorphism of the Bovine IFITM3 Gene Induces Differential Transcriptional Capacities of Hanwoo and Holstein Cattle.

Interferon-induced transmembrane protein 3 (IFITM3), a crucial effector of the host's innate immune system, prohibits an extensive range of viruses. Previous studies have reported that single nucleotide polymorphisms (SNPs) of the IFITM3 gene are associated with the expression level and length of the IFITM3 protein and can impact susceptibility to infectious viruses and the severity of infection with these viruses. However, there have been no studies on polymorphisms of the bovine IFITM3 gene. In the present study, we finely mapped the bovine IFITM3 gene and annotated the identified polymorphisms. We investigated polymorphisms of the bovine IFITM3 gene in 108 Hanwoo and 113 Holstein cattle using direct sequencing and analyzed genotype, allele, and haplotype frequencies and linkage disequilibrium (LD) between the IFITM3 genes of the two cattle breeds. In addition, we analyzed transcription factor-binding sites and transcriptional capacity using PROMO and luciferase assays, respectively. Furthermore, we analyzed the effect of a nonsynonymous SNP of the IFITM3 gene using PolyPhen-2, PANTHER, and PROVEAN. We identified 23 polymorphisms in the bovine IFITM3 gene and found significantly different genotype, allele, and haplotype frequency distributions and LD scores between polymorphisms of the bovine IFITM3 gene in Hanwoo and Holstein cattle. In addition, the ability to bind the transcription factor Nkx2-1 and transcriptional capacities were significantly different depending on the c.-193T > C allele. Furthermore, nonsynonymous SNP (F121L) was predicted to be benign. To the best of our knowledge, this is the first genetic study of bovine IFITM3 polymorphisms.

Interhemispheric Cortico-Cortical Pathway for Sequential Bimanual Movements in Mice.

Animals precisely coordinate their left and right limbs for various adaptive purposes. While the left and right limbs are clearly controlled by different cortical hemispheres, the neural mechanisms that determine the action sequence between them remains elusive. Here, we have established a novel head-fixed bimanual-press (biPress) sequence task in which mice sequentially press left and right pedals with their forelimbs in a predetermined order. Using this motor task, we found that the motor cortical neurons responsible for the first press (1P) also generate independent motor signals for the second press (2P) by the opposite forelimb during the movement transitions between forelimbs. Projection-specific calcium imaging and optogenetic manipulation revealed these motor signals are transferred from one motor cortical hemisphere to the other via corticocortical projections. Together, our results suggest the motor cortices coordinate sequential bimanual movements through corticocortical pathways.

Characterization of submicron aerosols over the Yellow Sea measured onboard the Gisang 1 research vessel in the spring of 2018 and 2019.

The physico-chemical properties of submicron aerosols were measured in the spring of 2018 and 2019 over the Yellow Sea onboard the Gisang 1 research vessel. Aerosol number concentrations in 2019 were slightly higher than those in 2018, and the mean number concentrations of particles larger than 10 nm and cloud condensation nuclei (CCN) at 0.6% supersaturation (S) in spring 2019 were 7312 ± 3807 cm-3 and 4816 ± 1692 cm-3, respectively. Aerosol concentrations in June were lower than those in April and May, which was considered to be due to the East Asian summer monsoon. Aerosol number concentrations and size distributions were significantly influenced by meteorological conditions, such as wind and relative humidity. Aitken and accumulation mode particles dominated the aerosol number size distributions over the Yellow Sea. A distinct new particle formation (NPF) and growth event was observed, the spatial extent of which was estimated to cover at least 200 km × 400 km of the Yellow Sea. The general characteristics of NPF and growth over the Yellow Sea were similar to those in rural areas. Aerosol number concentrations below 1000 cm-3 were recorded on extremely clean days. A CCN closure experiment conducted using previous measurement data showed good results, indicating that CCN concentrations can be estimated with good accuracy, and the hygroscopicity over the Yellow Sea was similar to that of aged continental aerosols.

The First Report of the Prion Protein Gene (PRNP) Sequence in Pekin Ducks (Anas platyrhynchos domestica): The Potential Prion Disease Susceptibility in Ducks.

Pathogenic prion protein (PrPSc), converted from normal prion protein (PrPC), causes prion disease. Although prion disease has been reported in several mammalian species, chickens are known to show strong resistance to prion diseases. In addition to chickens, the domestic duck occupies a large proportion in the poultry industry and may be regarded as a potential resistant host against prion disease. However, the DNA sequence of the prion protein gene (PRNP) has not been reported in domestic ducks. Here, we performed amplicon sequencing targeting the duck PRNP gene with the genomic DNA of Pekin ducks. In addition, we aligned the PrP sequence of the Pekin duck with that of various species using ClustalW2 and carried out phylogenetic analysis using Molecular Evolutionary Genetics Analysis X (MEGA X). We also constructed the structural modeling of the tertiary and secondary structures in avian PrP using SWISS-MODEL. Last, we investigated the aggregation propensity on Pekin duck PrP using AMYCO. We first reported the DNA sequence of the PRNP gene in Pekin ducks and found that the PrP sequence of Pekin ducks is more similar to that of geese than to that of chickens and mallards (wild ducks). Interestingly, Pekin duck PrP showed a high proportion of ß-sheets compared to that of chicken PrP, and a high aggregation propensity compared to that of avian PrPs. However, Pekin duck PrP with substitutions of chicken-specific amino acids showed reduced aggregation propensities. To the best of our knowledge, this is the first report on the genetic characteristics of the PRNP sequence in Pekin ducks.

Genetic association between the rs12252 SNP of the interferon-induced transmembrane protein gene and influenza A virus infection in the Korean population.

BACKGROUND: Interferon-induced transmembrane protein 3 (IFITM3) is a potent host antiviral effector protein that blocks the invasion of various viruses, including the influenza A virus (IAV). The C allele of the rs12252 single nucleotide polymorphism (SNP) shows vulnerability to the pandemic 2009 H1N1 IAV in European and Asian populations. OBJECTIVE: Here, we estimated the disease susceptibility of the rs12252 SNP with the pandemic 2009 H1N1 IAV infection in the Korean population. RESULTS: We carried out direct sequencing of the IFITM3 gene and compared the genotype and allele frequencies of the rs12252 SNP of the IFITM3 gene in healthy Koreans and pandemic 2009 H1N1 IAV-infected patients. Notably, we observed that healthy individuals had a similar genotype distribution of the rs12252 SNP (P = 0.140) as patients. The dominant model and recessive model did not find a statistically significant difference in genotype distribution between healthy individuals and patients. In addition, the allele distribution of the rs12252 SNP of in healthy individuals and patients also showed a similar genetic distribution (P = 0.757). However, the genetic distribution of rs12252 SNP in merged patient group (Koreans and Chinese populations) showed significant association with susceptibility of pandemic 2009 IAV (P = 0.0393). CONCLUSION: To the best of our knowledge, this was the first evaluation of the susceptibility of the pandemic 2009 H1N1 IAV in the Korean population.

Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells.

Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic targets, we investigated the mechanism of piperlongumine, a small molecule identified in a chemical library screen to specifically target cancer cells with a hyperactive mTORC1 phenotype. Sensitivity to piperlongumine was dependent on its ability to suppress RUVBL1/2-TTT, a complex involved in chromatin remodeling and DNA repair. Cancer cells with high mTORC1 activity are subjected to higher levels of DNA damage stress via c-Myc and displayed an increased dependency on RUVBL1/2 for survival and counteracting genotoxic stress. Examination of clinical cancer tissues also demonstrated that high mTORC1 activity was accompanied by high RUVBL2 expression. Our findings reveal a previously unknown role for RUVBL1/2 in cell survival, where it acts as a functional chaperone to mitigate stress levels induced in the mTORC1-Myc-DNA damage axis.