Little is known about the national colonoscopy volume in Asian countries. This study aimed to assess the national colonoscopy volume in Korea over a 12-year period on the basis of a nationwide population-based database.

Patients with stage II or III colorectal cancer (CRC) exhibit various clinical outcomes after radical treatments. The 5-year survival rate was between 50 and 87%. However, the underlying mechanisms of the variation remain unclear. Here we show that AMPKα1 is overexpressed in CRC patient specimens and the high expression is correlated with poor patient survival. We further reveal a previously unrecognized function of AMPKα1, which maintains high level of reduced glutathione to keep reduction-oxidation reaction (redox) homeostasis under stress conditions, thus promoting CRC cell survival under metabolic stress in vitro and enhancing tumorigenesis in vivo. Mechanistically, AMPKα1 regulate the glutathione reductase (GSR) phosphorylation possibly through residue Thr507 which enhances its activity. Suppression of AMPKα1 by using nano-sized polymeric vector induces a favorable therapeutic effect, especially when in combination with oxaliplatin. Our study uncovers a novel function of AMPKα1 in redox regulation and identifies a promising therapeutic strategy for treatment of CRC.

Microbiota play an important role in total tract nutrient digestion, especially when fibrous diets are fed to pigs. This study aimed to use metagenomics to predict faecal nutrient digestibility in grower-finisher pigs. The study design consisted of 160 three-way crossbreed grower-finisher pigs (80 female and 80 male) which were either fed a diet based on corn/soybean meal or a more fibrous diet based on wheat/barley/by-products. On the day before slaughter, faecal samples were collected and used to determine faecal digestibility of dry matter, ash, organic matter, crude protein, crude fat, crude fibre and non-starch polysaccharides. The faecal samples were also sequenced for the 16S hypervariable region of bacteria (V3/V4) to profile the faecal microbiome. With these data, we calculated the between-animal variation in faecal nutrient digestibility associated with variation in the faecal microbiome, that is the "microbiability". The microbiability values were significantly greater than zero for dry matter, organic matter, crude protein, crude fibre and non-starch polysaccharides, ranging from 0.58 to 0.93, as well as for crude fat with a value of 0.37, but not significantly different from zero for ash. Using leave-one-out cross-validation, we estimated the accuracy of predicting digestibility values of individual pigs based on their faecal microbiota composition. The accuracies of prediction for crude fat and ash digestibility were virtually 0, and for the other nutrients, the accuracies ranged from 0.42 to 0.63. In conclusion, the faecal microbiota composition gave high microbiability values for faecal digestibility of dry matter, organic matter, crude protein, crude fibre and non-starch polysaccharides. The accuracies of prediction are relatively low if the interest is in precisely predicting faecal nutrient digestibility of individual pigs, but are promising from the perspective of ranking animals in a genetic selection context.

Fluoroquinolones (FQ) form the backbone in experimental treatment regimens against drug-susceptible tuberculosis. However, little is known on whether the genetic variation present in natural populations of Mycobacterium tuberculosis (Mtb) affects the evolution of FQ-resistance (FQ-R). To investigate this question, we used nine genetically distinct drug-susceptible clinical isolates of Mtb and measured their frequency of resistance to the FQ ofloxacin (OFX) in vitro. We found that the Mtb genetic background led to differences in the frequency of OFX-resistance (OFX-R) that spanned two orders of magnitude and substantially modulated the observed mutational profiles for OFX-R. Further, in vitro assays showed that the genetic background also influenced the minimum inhibitory concentration and the fitness effect conferred by a given OFX-R mutation. To test the clinical relevance of our in vitro work, we surveyed the mutational profile for FQ-R in publicly available genomic sequences from clinical Mtb isolates, and found substantial Mtb lineage-dependent variability. Comparison of the clinical and the in vitro mutational profiles for FQ-R showed that 51% and 39% of the variability in the clinical frequency of FQ-R gyrA mutation events in Lineage 2 and Lineage 4 strains, respectively, can be attributed to how Mtb evolves FQ-R in vitro. As the Mtb genetic background strongly influenced the evolution of FQ-R in vitro, we conclude that the genetic background of Mtb also impacts the evolution of FQ-R in the clinic.

Our understanding of mesial temporal lobe epilepsy (MTLE), one of the most common form of drug-resistant epilepsy in humans, is derived mainly from clinical, imaging, and physiological data from humans and animal models. High-throughput gene expression studies of human MTLE have the potential to uncover molecular changes underlying disease pathogenesis along with novel therapeutic targets. Using RNA- and small RNA-sequencing in parrallel, we explored differentially expressed genes in the hippocampus and cortex of MTLE patients who had undergone surgical resection and non-epileptic controls. We identified differentially expressed genes in the hippocampus of MTLE patients and differentially expressed small RNAs across both the cortex and hippocampus. We found significant enrichment for astrocytic and microglial genes among up-regulated genes, and down regulation of neuron specific genes in the hippocampus of MTLE patients. The transcriptome profile of the small RNAs reflected disease state more robustly than mRNAs, even across brain regions which show very little pathology. While mRNAs segregated predominately by brain region for MTLE and controls, small RNAs segregated by disease state. In particular, our data suggest that specific miRNAs (e.g., let-7b-3p and let-7c-3p) may be key regulators of multiple pathways related to MTLE pathology. Further, we report a strong association of other small RNA species with MTLE pathology. As such we have uncovered novel elements that may contribute to the establishment and progression of MTLE pathogenesis and that could be leveraged as therapeutic targets.

Flowering is a prerequisite for pear fruit production. Therefore, the development of flower buds and the control of flowering time are important for pear trees. However, the molecular mechanism of pear flowering is unclear. SOC1, a member of MADS-box family, is known as a flowering signal integrator in Arabidopsis. We identified eight SOC1-like genes in Pyrus bretschneideri and analyzed their basic information and expression patterns. Some pear SOC1-like genes were regulated by photoperiod in leaves. Moreover, the expression patterns were diverse during the development of pear flower buds. Two members of the pear SOC1-like genes, PbSOC1d and PbSOC1g, could lead to early flowering phenotype when overexpressed in Arabidopsis. PbSOC1d and PbSOC1g were identified as activators of the floral meristem identity genes AtAP1 and AtLFY and promote flowering time. These results suggest that PbSOC1d and PbSOC1g are promoters of flowering time and may be involved in flower bud development in pear.

Limited data are available regarding psychosocial distress at the time of diagnosis of ulcerative colitis (UC). We investigated the psychosocial burden and factors related to poor health-related quality of life (HRQL) among patients newly diagnosed with moderate-to-severe UC who were affiliated with the nationwide prospective cohort study.

Early degenerative changes of articular cartilage are detected using contrast-enhanced computed tomography (CT) with a cationic contrast agent (CA). However, cationic CA diffusion into degenerated cartilage decreases with proteoglycan depletion and increases with elevated water content, thus hampering tissue evaluation at early diffusion time points. Furthermore, the contrast at synovial fluid-cartilage interface diminishes as a function of diffusion time hindering accurate cartilage segmentation. For the first time, we employ quantitative dual-energy CT (QDECT) imaging utilizing a mixture of three CAs (cationic CA4+ and non-ionic gadoteridol which are sensitive to proteoglycan and water contents, respectively, and bismuth nanoparticles which highlight the cartilage surface) to simultaneously segment the articulating surfaces and determine of the cartilage condition. Intact healthy, proteoglycan-depleted, and mechanically injured bovine cartilage samples (n = 27) were halved and imaged with synchrotron microCT 2-h post immersion in triple CA or in dual CA (CA4+ and gadoteridol). CA4+ and gadoteridol partitions were determined using QDECT, and pairwise evaluation of these partitions was conducted for samples immersed in dual and triple CAs. In conclusion, the triple CA method is sensitive to proteoglycan depletion while maintaining sufficient contrast at the articular surface to enable detection of cartilage lesions caused by mechanical impact.

Objective This study aimed to present the impact of age and gender on thyroid hormone levels in a large Chinese population with sufficient iodine intake. Subjects and methods A total of 83643 individuals were included and were stratified by age and gender. The median, 2.5th and 97.5th of thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4) and FT3/FT4 ratio were calculated for both genders for every decade from 18 to over 80 years. TSH, FT3, FT4, FT3/FT4 distribution in each age group was evaluated for females and males using smoothing splines in the generalized additive models (GAM). TSH concentrations were compared in the different age groups in gender. Results In the over 80s age group, the TSH level (median: 2.57 mIU/L, 2.5th-97.5th: 0.86-7.56 mIU/L) was significantly higher than other age groups, irrespective to gender (P<0.001). Females had a higher TSH value than males in all age groups (P<0.001). Results of the smoothing curves showed that TSH increased with age, FT3 concentration was higher in males than in females and the tendency of the FT3/FT4 ratio was basically similar to that of FT3. TSH concentration in the 50s age group (median 2.48 mIU/L for females versus 2.00 mIU/L for males) was significantly higher than that in the 30s age group (median 2.18 mIU/L for females versus median 1.85 mIU/L for males). Conclusions In accord with increasing TSH values during aging, females and older adults have lower FT3 values and lower FT3/FT4 ratios, while the FT4 values remain stable.

Ximenia americana L. is popularly known as yellow plum, brave plum or tallow wood. All the parts of this plant are used in popular medicine. Its reddish and smooth bark are used to treat skin infections, inflammation of the mucous membranes and in the wound healing process.

Corni Fructus (CF), the red fruit of Cornus officinalis Siebold & Zucc, has been used both as food and medicinal herb in traditional Chinese medicine (TCM). Loganin is a major iridoid glycoside and one of the quality control indexes of CF. In TCM clinical practice, prescription containing CF is commonly used to treat osteoarthritis (OA), but the underlying mechanisms of loganin are not yet utterly understood.

Late gene transcription in the beta- and gammaherpesviruses depends on a set of virally encoded transcriptional activators (vTAs) that hijack the host transcriptional machinery and direct it to a subset of viral genes that are required for completion of the viral replication cycle and capsid assembly. In Kaposi's sarcoma-associated herpesvirus (KSHV), these vTAs are encoded by ORF18, ORF24, ORF30, ORF31, ORF34, and ORF66. Assembly of the vTAs into a complex is critical for late gene transcription, and thus, deciphering the architecture of the complex is central to understanding its transcriptional regulatory activity. Here, we generated an ORF66-null virus and confirmed that it fails to produce late genes and infectious virions. We show that ORF66 is incorporated into the vTA complex primarily through its interaction with ORF34, which is dependent upon a set of four conserved cysteine-rich motifs in the C-terminal domain of ORF66. While both ORF24 and ORF66 occupy the canonical K8.1 late gene promoter, their promoter occupancy requires the presence of the other vTAs, suggesting that sequence-specific, stable binding requires assembly of the entire complex on the promoter. Additionally, we found that ORF24 expression is impaired in the absence of a stable vTA complex. This work extends our knowledge about the architecture of the KSHV viral preinitiation complex and suggests that it functions as a complex to recognize late gene promoters.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) is an oncogenic gammaherpesvirus that is the causative agent of multiple human cancers. The release of infectious virions requires the production of capsid proteins and other late genes, whose production is transcriptionally controlled by a complex of six virally encoded proteins that hijack the host transcription machinery. It is poorly understood how this complex assembles or what function five of its six components play in transcription. Here, we demonstrate that ORF66 is an essential component of this complex in KSHV and that its inclusion in the complex depends upon its C-terminal domain, which contains highly conserved cysteine-rich motifs reminiscent of zinc finger motifs. Additionally, we examined the assembly of the viral preinitiation complex at late gene promoters and found that while sequence-specific binding of late gene promoters requires ORF24, it additionally requires a fully assembled viral preinitiation complex.

Feeding behavior regulation is a complex process, which depends on the central integration of different signals, such as glucose, leptin, and ghrelin. Recent studies have shown that glial cells known as tanycytes that border the basal third ventricle (3V) detect glucose and then use glucose-derived signaling to inform energy status to arcuate nucleus (ARC) neurons to regulate feeding behavior. Monocarboxylate transporters (MCT) 1 and MCT4 are localized in the cellular processes of tanycytes, which could facilitate monocarboxylate release to orexigenic and anorexigenic neurons. We hypothesize that MCT1 and MCT4 inhibitions could alter the metabolic communication between tanycytes and ARC neurons, affecting feeding behavior. We have previously shown that MCT1 knockdown rats eat more and exhibit altered satiety parameters. Here, we generate MCT4 knockdown rats and MCT1-MCT4 double knockdown rats using adenovirus-mediated transduction of a shRNA into the 3V. Feeding behavior was evaluated in MCT4 and double knockdown animals, and neuropeptide expression in response to intracerebroventricular glucose administration was measured. MCT4 inhibition produced a decrease in food intake, contrary to double knockdown. MCT4 inhibition was accompanied by a decrease in eating rate and mean meal size and an increase in mean meal duration, parameters that are not changed in the double knockdown animals with exception of eating rate. Finally, we observed a loss in glucose regulation of orexigenic neuropeptides and abnormal expression of anorexigenic neuropeptides in response to fasting when these transporters are inhibited. Taken together, these results indicate that MCT1 and MCT4 expressions in tanycytes play a role in feeding behavior regulation.

SARI (suppressor of AP-1, regulated by IFN) impaired tumour growth by promoting apoptosis and inhibiting cell proliferation and tumour angiogenesis in various cancers. However, the role of SARI in regulating tumour-associated inflammation microenvironment is still elusive. In our study, the colitis-dependent and -independent primary model were established in SARI deficiency mice and immuno-reconstructive mice to investigate the functional role of SARI in regulating tumour-associated inflammation microenvironment and primary colon cancer formation. The results have shown that SARI deficiency promotes colitis-associated cancer (CAC) development only in the presence of colon inflammation. SARI inhibited tumour-associated macrophages (TAM) infiltration in colon tissues, and SARI deficiency in bone marrow cells has no observed role in the promotion of intestinal tumorigenesis. Mechanism investigations indicated that SARI down-regulates p-STAT1 and STAT1 expression in colon cancer cells, following inhibition of MCP-1/CCR2 axis activation during CAC development. Inverse correlations between SARI expression and macrophage infiltration, MCP-1 expression and p-STAT1 expression were also demonstrated in colon malignant tissues. Collectively, our results prove the inhibition role of SARI in colon cancer formation through regulating TAM infiltration.

Competition is a major type of interaction between fungi and bacteria in soil and is also an important factor in suppression of plant diseases caused by soil-borne fungal pathogens. There is increasing attention for the possible role of volatiles in competitive interactions between bacteria and fungi. However, knowledge on the actual role of bacterial volatiles in interactions with fungi within soil microbial communities is lacking. Here, we examined colonization of sterile agricultural soils by fungi and bacteria from non-sterile soil inoculums during exposure to volatiles emitted by soil-derived bacterial communities. We found that colonization of soil by fungi was negatively affected by exposure to volatiles emitted by bacterial communities whereas that of bacteria was barely changed. Furthermore, there were strong effects of bacterial community volatiles on the assembly of fungal soil colonizers. Identification of volatile composition produced by bacterial communities revealed several compounds with known fungistatic activity. Our results are the first to reveal a collective volatile-mediated antagonism of soil bacteria against fungi. Given the better exploration abilities of filamentous fungi in unsaturated soils, this may be an important strategy for bacteria to defend occupied nutrient patches against invading fungi. Another implication of our research is that bacterial volatiles in soil atmospheres can have a major contribution to soil fungistasis.

Convergent gene pairs can produce transcripts with complementary sequences. We had shown that mRNA duplexes form in vivo in Saccharomyces cerevisiae via interactions of mRNA overlapping 3'-ends and can lead to posttranscriptional regulatory events. Here we show that mRNA duplex formation is restricted to convergent genes separated by short intergenic distance, independently of their 3'-untranslated region (UTR) length. We disclose an enrichment in genes involved in biological processes related to stress among these convergent genes. They are markedly conserved in convergent orientation in budding yeasts, meaning that this mode of posttranscriptional regulation could be shared in these organisms, conferring an additional level for modulating stress response. We thus investigated the mechanistic advantages potentially conferred by 3'-UTR mRNA interactions. Analysis of genome-wide transcriptome data revealed that Pat1 and Lsm1 factors, having 3'-UTR binding preference and participating to the remodeling of messenger ribonucleoprotein particles, bind differently these messenger-interacting mRNAs forming duplexes in comparison to mRNAs that do not interact (solo mRNAs). Functionally, messenger-interacting mRNAs show limited translational repression upon stress. We thus propose that mRNA duplex formation modulates the regulation of mRNA expression by limiting their access to translational repressors. Our results thus show that posttranscriptional regulation is an additional factor that determines the order of coding genes.

Canine parvovirus type 2 (CPV-2) emerged suddenly in the late 1970s as pathogen of dogs, causing a severe and often fatal gastroenteric disease. The original CPV-2 was replaced by three antigenic variants, CPV-2a, CPV-2b and CPV-2c, which to date have gained a worldwide distribution with different relative proportions. All previous studies conducted in Africa were based on partial VP2 gene sequences. The aim of this study was to provide a genome analysis to characterize the CPV strains collected in Nigeria, Africa. Rectal swab samples (n = 320) were collected in 2018 and tested by means of an immunochromatographic assay. Among the 144 positive samples, 59 were selected for further analyses using different molecular assays. The results revealed a high prevalence of CPV-2c (91.5%) compared to the CPV-2a variant (8.5%). The VP2 gene sequences showed a divergence from the strains analysed in 2010 in Nigeria and a closer connection with CPV strains of Asian origin. The non-structural gene analysis evidenced amino acid changes never previously reported. The molecular analysis based on genomic sequences evidenced a geographical pattern of distribution of the analysed strains, suggesting a potential common evolutionary origin with CPV of Asian origin. This study represents the first CPV molecular characterization including all the encoding gene sequences conducted in the African continent and contributes to define the current geographical spread of the CPV variants worldwide.

To eradicate human immunodeficiency virus type 1 (HIV-1) infection, a comprehensive strategy including preventive vaccine development is needed. Envelope glycoproteins (Env) play a central role in viral infection and are the major targets of humoral immune responses. Therefore, Env is a candidate vaccine antigen, and its characterization is necessary for vaccine development. The characterization of the transmitted/founder (T/F; i.e., recently infected) virus that is responsible for the establishment of infection and induction of primary anti-HIV-1 immune responses is important. We herein established HIV-1 env clones derived from recently infected Indonesian individuals. All env genes were classified into CRF01_AE. The immunological characterization of env clones was performed by neutralization tests using a series of broadly neutralizing antibodies. The present study is the first to immunologically characterize the CRF01_AE T/F virus circulating in Indonesia.

The contribution of the pleiotropic hormone Prolactin (PRL) to several physiological and pathological processes is still unknown. To clarify the role of PRL in these processes during the last decade, different human PRL antagonists have been produced to either partially or fully block the wild type hormone activity. In this work, we have cloned these wild type and antagonist sequences in lentivectors (LV) to express them as recombinant self-processing polypeptides by employing a P2A sequence (hPRL-P2A-GFP). We show that these LVs can efficiently transduce and express the hPRL proteins in different cell types and that the P2A sequence does not affect their activities. Additionally, we have tested their activities in paracrine and autocrine cell culture experiments. Our results demonstrate that these recombinant hPRL-P2A proteins are bioactive in both paracrine and autocrine modes, highlighting the potential usefulness of these hPRL-containing LVs for determining the contribution of hPRL to different biological processes.

Cocoa extracts rich in polyphenols are used as potential agent for treating diabetes. Cocoa polyphenols have been proved to ameliorate important hallmarks of type-2 diabetes (T2D). They can regulate glucose levels by increasing insulin secretion, promoting β-cell proliferation and a reduction of insulin resistance. In addition, epidemiological evidence indicates that consumption of flavonoid decreases the incidence of T2D.