Antisense oligonucleotides (ASOs) are a novel therapeutic approach to target difficult-to-drug protein classes by targeting their corresponding mRNAs. Significantly enhanced ASO activity has been achieved by the targeted delivery of ASOs to selected tissues. One example is the targeted delivery of ASOs to hepatocytes, achieved with N-acetylgalactosamine (GalNAc) conjugation to ASO, which results in selective uptake by asialoglycoprotein receptor (ASGR). Here we have evaluated the potential of GalNAc-conjugated ASOs as a therapeutic approach to targeting difficult-to-drug pathways in hepatocellular carcinoma (HCC). The activity of GalNAc-conjugated ASOs was superior to that of the unconjugated parental ASO in ASGR (+) human HCC cells in vitro, but not in ASGR (-) cells. Both human- and mouse-derived HCC displayed reduced levels of ASGR, however, despite this, GalNAc-conjugated ASOs showed a 5- to 10-fold increase in potency in tumors. Systemically administered GalNAc-conjugated ASOs demonstrated both enhanced antisense activity and antitumor activity in the diethylnitrosamine-induced HCC tumor model. Finally, GalNAc conjugation enhanced ASO activity in human circulating tumor cells from HCC patients, demonstrating the potential of this approach in primary human HCC tumor cells. Taken together, these results provide a strong rationale for a potential therapeutic use of GalNAc-conjugated ASOs for the treatment of HCC.

Female sexual dysfunction (FSD) is a common endocrine disease that impairs the quality of life for many women. The existing therapy strategies still have many disadvantages. It is necessary to explore new pharmacologic treatments that are effective and safe.

Fate-changing transcription factors (TFs) scan chromatin to initiate new genetic programs during cell differentiation and reprogramming. Yet the protein structure domains that allow TFs to target nucleosomal DNA remain unexplored. We screened diverse TFs for binding to nucleosomes containing motif-enriched sequences targeted by pioneer factors in vivo. FOXA1, OCT4, ASCL1/E12α, PU1, CEBPα, and ZELDA display a range of nucleosome binding affinities that correlate with their cell reprogramming potential. We further screened 593 full-length human TFs on protein microarrays against different nucleosome sequences, followed by confirmation in solution, to distinguish among factors that bound nucleosomes, such as the neuronal AP-2α/β/γ, versus factors that only bound free DNA. Structural comparisons of DNA binding domains revealed that efficient nucleosome binders use short anchoring α helices to bind DNA, whereas weak nucleosome binders use unstructured regions and/or β sheets. Thus, specific modes of DNA interaction allow nucleosome scanning that confers pioneer activity to transcription factors.

Ubiquitin (Ub) is a small protein that post-translationally modifies a variety of substrates in eukaryotic cells to modulate substrate function. The ability of Ub to interact with numerous protein domains makes Ub an attractive scaffold for engineering ubiquitin variants (UbVs) with high target specificity. Previously, we identified a UbV that formed a non-covalent stable dimer via a β-strand exchange, and in the current work we identified and characterized the minimal substitutions in the primary sequence of Ub required to form a higher ordered complex. Using solution angle scattering and X-ray crystallography, we show that a single substitution of residue Gly10 to either Ala or Val is sufficient to convert Ub from a monomer to a dimer. We also investigate contributions to dimer formation by the residues in the surrounding sequence. These results can be used to develop next-generation phage-display libraries of UbVs to engineer new interfaces for protein recognition.

Spontaneous brain activity as assessed with resting-state fMRI exhibits rich spatiotemporal structure. However, the principles by which brain-wide patterns of spontaneous fMRI activity reconfigure and interact with each other remain unclear. We used a framewise clustering approach to map spatiotemporal dynamics of spontaneous fMRI activity with voxel resolution in the resting mouse brain. We show that brain-wide patterns of fMRI co-activation can be reliably mapped at the group and subject level, defining a restricted set of recurring brain states characterized by rich network structure. Importantly, we document that the identified fMRI states exhibit contrasting patterns of functional activity and coupled infraslow network dynamics, with each network state occurring at specific phases of global fMRI signal fluctuations. Finally, we show that autism-associated genetic alterations entail the engagement of atypical functional states and altered infraslow network dynamics. Our results reveal a novel set of fundamental principles guiding the spatiotemporal organization of resting-state fMRI activity and its disruption in brain disorders.

Patients' adherence to therapeutic regimes may be influenced by subjective beliefs about chronic conditions. One of the challenges for health professionals in enhancing adherence is taking patients' understanding into account when giving health advice and/or providing medical treatment.

The phenomenon that cancer cells avidly exhibit glycolysis with lactate secretion and decrease in mitochondrial activity under aerobic conditions is known historically as the Warburg effect. Rho GTPase-activating protein 4 (ARHGAP4) is an important negative regulator of the Rho signaling pathway that was associated with the tumorigenesis. Our study aims to determine the function of ARHGAP4 in controlling the glycolytic process of pancreatic cancer in vitro and possible molecular mechanism involved.

Purpose: The chemotherapeutic regimen DCAG (decitabine with cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor) is effective for elderly patients with acute myeloid leukemia, but recommendations for young patients remain controversial. This study investigated the tolerance and efficacy of DCAG for patients with newly diagnosed acute myeloid leukemia (aged 14-60 years). The clinical features or molecular markers that may predict response to DCAG were identified. Patients and methods: One-hundred sixty-one consecutive patients with newly diagnosed acute myelogenous leukemia received DCAG or standard (idarubicin plus cytarabine, IA) induction chemotherapy (n=64 and 97, respectively). Results: The rates of complete remission after the first cycle, overall survival (OS), and event-free survival (EFS) were comparable. After the second cycle, the complete remission rate of the DCAG group (54.7%) was significantly lower than that of the reference (78.35%, P=0.005). The following were associated with significantly worse OS, and EFS, in the DCAG group: Eastern Cooperative Oncology Group (ECOG) score ≥3 and no response after the second induction therapy; and FLT3-ITD. The multivariate analysis showed the DCAG group with significantly shorter OS associated with ECOG ≥3 and FLT3-ITD. In the DCAG group, after the first cycle of induction chemotherapy the median recovery times of neutrophils and platelets were 15.8 and 13 days. Conclusion: The DCAG and IA groups were similar with regard to complete remission rate after the first cycle, OS, and EFS. The complete remission rate after the second cycle of the DCAG was significantly lower than that of the IA. Grade 4 neutropenia and thrombocytopenia were a major adverse event associated with DCAG.

This study was designed to explore the regulation mechanism of miR-450 in the development of hepatocarcinoma, and the effects of overexpression of miR-450 on biological behaviors such as proliferation, migration, and invasion of hepatoma cells.

Hepatocellular carcinoma (HCC) is the second leading cause of death among cancers worldwide. In this study, we aimed to identify the molecular target genes and detect the key mechanisms of HCC. Three gene expression profiles (GSE84006, GSE14323, GSE14811) and two miRNA expression profiles (GSE40744, GSE36915) were analyzed to determine the molecular target genes, microRNAs (miRNAs) and the potential molecular mechanisms in HCC.

Background: Previous studies have reported that the albumin-to-alkaline phosphatase ratio (AAPR), a novel blood biomarker-based index, is associated with clinical outcome in several cancers. However, data relating to lung cancer are rare. This study was performed to clarify the clinical significance of AAPR in patients with metastatic non-small-cell lung cancer (NSCLC). Methods: In total, 290 stage IV NSCLC patients were enrolled in this retrospective study. Associations between serum enzyme levels and clinical characteristics were analyzed using the Mann-Whitney U-test or chi-squared test. Kaplan-Meier survival analysis and Cox's proportional hazard regression model were adopted to assess the prognostic value of AAPR for overall survival (OS). Results: The optimal cut-off points for AAPR and lactate dehydrogenase (LDH) were 0.36 and 265.5 U/L, respectively. Patients with AAPR ≤0.36 had apparently longer survival than those with AAPR >0.36 (13 vs 7 months, P<0.001). Furthermore, AAPR was an independent predictor of OS in metastatic NSCLC in multivariate analysis (HR=0.657, 95% CI=0.504-0.856, P<0.01). The prognostic impact of LDH for survival of NSCLC populations was also validated in this study (HR=1.462, 95% CI=1.070-1.999, P<0.05). Conclusion: Elevated AAPR can be an independent favorable prognostic indicator in metastatic NSCLC.

The worldwide dissemination of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae has become a major health concern. Previous studies have shown that psychoactive drugs have intrinsic antimicrobial activity and may play a role in the dissemination of antibiotic resistance. The objective of this study was to assess the association between prescriptions for psychoactive drug and urine colonization with ESBL-producing Enterobacteriaceae.

The Tribe Wisterieae (Zhu 1994), founded on the single genus Wisteria, is emended and recircumscribed based on morphology and data from nuclear ITS and ndhJ-trnF, matK and rbcL chloroplast DNA sequences. This newly enlarged tribe comprises 36 species and 9 infraspecific taxa within 13 described genera. Six genera are new, two are reinstated and five were previously placed in Tribe Millettieae. The genus Adinobotrys is also reinstated comprising two species including the new combination A.vastus. Other reinstated genera include Whitfordiodendron, with four species, and Padbruggea, with three species, including the reinstatement of P.filipes and the new combination P.filipesvar.tomentosa. The existing genera Afgekia, Callerya, Endosamara (with the new combination E.racemosavar.pallida), Sarcodum and Wisteria, with the new combinations W.frutescenssubsp.macrostachya are evaluated. The new genera comprise three Australasian species in Austrocallerya: A.australis, A.megasperma and A.pilipes; Wisteriopsis with five species from east Asia has six new combinations: W.japonica, W.kiangsiensis, W.championii, W.eurybotrya, W.reticulata and W.reticulatavar.stenophylla. Two species comprise the new Thai genus Kanburia: K.tenasserimensis and K.chlorantha. Nanhaia comprises the two species: N.fordii and N.speciosa and the monotypic genera Sigmoidala and Serawaia are based respectively on the species S.kityana and S.strobilifera. Lectotypes are designated for the names Adinobotrysfilipes, A.myrianthus, Millettiabonatiana, Millettiabracteosa, Millettiachampionii, Millettiacinerea, Millettiadielsiana, Millettiakityana, M.maingayi, Millettianitida, Millettiaoocarpa, Millettiapurpurea, M.reticulata, M.reticulatavar.stenophylla, Padbruggeadasyphylla, Pterocarpusaustralis, Robiniaracemosa, Whitfordiodendronscandens, W.sumatranum and Wisteriapallida. A neotype is designated for the name Millettialeiogyna.

Verdesmummenglaense (C. Chen & X. J. Cui) H. Ohashi & K. Ohashi is a rare species in the tribe Desmodieae (Fabaceae) from Southwest China. The morphological observation shows that the species has minute capitate stigma and ebracteolate calyces, which are entirely different from the funnel-shaped stigma and bracteolate calyces of the genus Verdesmum H. Ohashi & K. Ohashi, but are consistent with those of the genus Hylodesmum H. Ohashi & R. R. Mill. The generic placement of V.menglaense within Hylodesmum was further supported by molecular evidence. Therefore, this species should be returned to Hylodesmum as H.menglaense (C. Chen & X. J. Cui) H. Ohashi & R. R. Mill. A full description including floral characters, a colour plate and a distribution map are first provided here for this species. After excluding the solo representative in China, Verdesmum should be removed from the record in Flora of China.

Santolina corsica Jord. & Fourr. Corsican-Sardinian is an endemism almost present all around Corsica; in Sardinia, it can only be found in Monte Albo (calcareous substratum and poor in nutrients). The aim of our study is to investigate the chemical composition of S. corsica essential oils from plants growing in three different stations located at different altitudes and evaluate the biological activity using anti-inflammatory, antioxidant and antimicrobial test. The composition of the essential oils was determined by gas chromatography and gas chromatography/mass spectrometry. The essential oils of the Sardinian-Corsican endemism S. corsica, growing in Monte Albo, showed a great variability, probably due to genetic characters different from the Corsican type. We found three different chemotypes: artemisia ketone-β-fellendrene; myrcene and β-fellandrene-myrcene. Standard microbiological assays demonstrated that the essential oils collected in the selected stations, compared with oil and compound with demonstrated antibacterial activity, don't have any antibacterial activity. DPPH test carried out on the tree samples, compared with chatechin, demonstrated that the oils don't have antioxidant activity. Regarding anti-inflammatory activity the study demonstrated that the essential oils have a good anti-inflammatory activity on the bronchial tract. The addition of essential oil make easy the exocytose and the histiocytes can expel the anthracotic pigment into the culture medium, purifying its cytoplasm and restoring its ability to phagocytize more material. With a higher concentration of granulocytes in the sample, the incubation of cells shows a non-specific inflammatory pattern in which the addition of the essential oils has a positive impact on the decrease of granulocytes. More experiments are requested to confirm the data, but on the basis of these first results S. corsica essential oil showed potential activity against respiratory infections.

Bacterial lipolytic enzymes represent an important class of proteins: they provide their host species with access to additional resources and have multiple applications within the biotechnology sector. Since the formalisation of lipolytic enzymes into families and subfamilies, advances in molecular biology have led to the discovery of lipolytic enzymes unable to be classified via the existing system. Utilising sequence-based comparison methods, we have integrated these novel families within the classification system so that it now consists of 35 families and 11 true lipase subfamilies. Representative sequences for each family and subfamily have been defined as well as methodology for accurate comparison of novel sequences against the reference proteins, facilitating the future assignment of novel proteins. Both the code and protein sequences required for integration of additional families are available at: https://github.com/thh32/Lipase_reclassification.

The overall anatomy of the genus Syllis (Annelida: Syllidae) has been largely studied; however, an integrative approach considering different anatomical techniques has never been considered. Here, we use micro-computed X-ray tomography (micro-CT) to examine the internal anatomy of Syllis gracilis Grube, 1840, along with other widely available techniques.

Mobile instant messaging services are being increasingly used for educational purposes, but their effectiveness in medical education is not well known. We assessed whether students' use of Kakao Talk (a mobile instant messaging service) during the early period of a week of clinical education influenced its use for academic purposes during a later period of the same week.

A high diversity of culturable foliar endophytic fungi is known from various mangrove plants, and the core taxa include species from Colletotrichum, Pestalotiopsis, Phoma, Phomopsis, Sporomiella, among others. Since a small fraction of fungi is able to grow in culture, this study investigated the diversity of fungi associated with leaves of Acanthus ilicifolius var. xiamenensis using both isolation and metabarcoding approaches. A total of 203 isolates were cultured from surface-sterilized leaves, representing 47 different fungal species: 30 species from the winter samples (104 isolates), and 26 species from the summer samples (99 isolates). Ascomycota was dominant in both types of leaf samples, while Basidiomycota was isolated only from the summer samples. Drechslera dematioidea (10.58%, percentage of occurrence), Colletotrichum sp. 3 (7.69%) and Alternaria sp. (7.69%) were dominant in the winter samples; Fusarium oxysporum (13.13%), Diaporthe endophytica (10.10%) and Colletotrichum sp. 1 (9.09%) in the summer samples. Overall, Corynespora cassiicola (6.90%), F. oxysporum (6.40%) and Guignardia sp. (6.40%) had the highest overall percentage of occurrence. In the metabarcoding analysis, a total of 111 operational taxonomic units (OTUs) were identified from 17 leaf samples: 96 OTUs from the winter and 70 OTUs from the summer samples. Sequences belonging to Ascomycota and Basidiomycota were detected in both samples but the former phylum was dominant over the latter. Based on read abundance, taxa having the highest percentage of occurrence included Alternaria sp. (3.46%), Cladosporium delicatulum (2.56%) and Pyrenochaetopsis leptospora (1.41%) in the winter leaves, and Aureobasidium sp. (10.72%), Cladosporium sp. (7.90%), C. delicatulum (3.45%) and Hortaea werneckii (3.21%) in the summer leaves. These latter four species also had the highest overall percentage of occurrence. Combining the results from both methods, a high diversity of fungi (at least 110 species) was found associated with leaves of A. ilicifolius var. xiamenensis. Many of the fungi identified were plant pathogens and may eventually cause diseases in the host.

The actinomycetes strains isolated from unexplored ecosystems are a promising alternative for the biosynthesis of novel antimicrobial compounds. Depending on the interesting antifungal activity of the studied strain S19, the statistical method seems to be an effective tool for optimizing the production of anticandidal molecules.