In order to clarify the influence of aromatic structure and COOH substitution of aromatic acids on their sorption to biochars, benzoic acid (BA), phthalic acid (PA), hemimellitic acid (HA), 2-biphenylcarboxylic acid (2-BA), 1-naphthoic acid (1-NA) and naphthalene were selected as model sorbates. Batch experiments on sorption of them to wheat straw-derived biochars at 300 °C (WS300) and 700 °C (WS700) were conducted. Results showed that WS700 with higher specific surface area and pore volume had faster and higher sorption of aromatic acids than WS300. Sorption affinity of aromatic acids decreased with increasing number of aromatic rings (BA > 1-NA > 2-BA), and was weakened by COOH substitution (BA > PA > HA). This was likely due to the π-electron delocalization into additional ring, reduced contact area of nonplanar aromatic structure on biochar surfaces, size exclusion of larger molecules in smaller pores of biochars and decreased hydrophobicity of aromatic acids by COOH substitution that abated the sorption. Dissociation of COOH substitution of aromatic acids also weakened their sorption to biochars due to the lower hydrophobicity of anionic species, and electrostatic repulsion between anionic species and negatively charged surface of biochars.

Phantom limb pain (PLP) is commonly considered to be a result of maladaptive brain plasticity. This model proposes that PLP is mainly caused by reorganisation in the primary somatosensory cortex, presumably characterised by functional degradation of the missing hand representation and remapping of other body part representations. In the current study, we replicate our previous results by showing that chronic PLP correlates with maintained representation of the missing hand in the primary sensorimotor missing hand cortex. We asked unilateral upper-limb amputees to move their phantom hand, lips or other body parts and measured the associated neural responses using functional magnetic resonance imaging (fMRI). We confirm that amputees suffering from worse chronic PLP have stronger activity in the primary sensorimotor missing hand cortex while performing phantom hand movements. We find no evidence of lip representation remapping into the missing hand territory, as assessed by measuring activity in the primary sensorimotor missing hand cortex during lip movements. We further show that the correlation between chronic PLP and maintained representation of the missing hand cannot be explained by the experience of chronic non-painful phantom sensations or compensatory usage of the residual arm or an artificial arm (prosthesis). Together, our results reaffirm a likely relationship between persistent peripheral inputs pertaining to the missing hand representation and chronic PLP. Our findings emphasise a need to further study the role of peripheral inputs from the residual nerves to better understand the mechanisms underlying chronic PLP.

There are different and complicated associations between genes and diseases. Finding the causal associations between genes and specific diseases is still challenging. In this work we present a method to predict novel associations of genes and pathways with inflammatory bowel disease (IBD) by integrating information of differential gene expression, protein-protein interaction and known disease genes related to IBD.

Genomic methods can provide extraordinary tools to explore the genetic background of wild species and domestic breeds, optimize breeding practices, monitor and limit the spread of recessive diseases, and discourage illegal crossings. In this study we analysed a panel of 170k Single Nucleotide Polymorphisms with a combination of multivariate, Bayesian and outlier gene approaches to examine the genome-wide diversity and inbreeding levels in a recent wolf x dog cross-breed, the Czechoslovakian Wolfdog, which is becoming increasingly popular across Europe.

Nitrogen (N) is a key macronutrient essential for plant growth, and its availability has a strong influence on crop development. The application of synthetic N fertilizers on crops has increased substantially in recent decades; however, the applied N is not fully utilized due to the low N use efficiency of crops. To overcome this limitation, it is important to understand the genome-wide responses and functions of key genes and potential regulatory factors in N metabolism.

The prothoracic gland (PG), the principal steroidogenic organ of insects, has been proposed as a model for steroid hormone biosynthesis and regulation.

Certainty of paternity is considered an important factor in the evolution of paternal care. Several meta-analyses across birds support this idea, particularly for species with altricial young. However, the role of certainty of paternity in the evolution and maintenance of exclusive paternal care in the black coucal (Centropus grillii), which is the only known altricial bird species with male-only care, is not well understood. Here we investigated whether the differences in levels of paternal care in the black coucal and its sympatric congener, the bi-parental white-browed coucal (Centropus superciliosus), are shaped by extra-pair paternity.

The term health literacy refers to the abilities and resources required to find, understand and use health information in managing health. This definition is reflected in the recent development of multidimensional health literacy tools that measure multiple facets of health literacy. The aim of this study was to determine the health literacy profile of a randomly selected, population-based sample of Australian women using a multidimensional tool, the Health Literacy Questionnaire (HLQ). A second aim was to investigate associations between independent HLQ scales, sociodemographic characteristics and lifestyle and anthropometric risk factors for chronic disease.

Pregnant women frequently show low-density Plasmodium infections that require more sensitive methods for accurate diagnosis and early treatment of malaria. This is particularly relevant in low-malaria transmission areas, where intermittent preventive treatment is not recommended. Molecular methods, such as polymerase chain reaction (PCR) are highly sensitive, but require sophisticated equipment and advanced training. Instead, loop mediated isothermal amplification (LAMP) provides an opportunity for molecular detection of malaria infections in remote endemic areas, outside a reference laboratory. The aim of the study is to evaluate the performance of LAMP for the screening of malaria in pregnant women in Colombia.

Continuous non-invasive urinary bladder volume measurement (cystovolumetry) would allow better management of urinary tract disease. Electrical impedance tomography (EIT) represents a promising method to overcome the limitations of non-continuous ultrasound measurements. The aim of this study was to compare the measurement accuracy of EIT to standard ultrasound in healthy volunteers.

Increasing evidence suggests heat stress induced chronic kidney disease (CKD) may be mediated by endogenous fructose generation and may be exacerbated by rehydration by fructose-containing solutions. We have recently reported a model of CKD induced by heat stress. Here we test the hypothesis that rehydration with fructose may induce worse kidney injury than rehydration with equal amounts of water, and we also test if this fructose-induced injury is associated with activation of inflammasomes in the kidney.

All patients with diabetes are at risk of developing diabetic retinopathy (DR), a progressive and potentially blinding condition. Early treatment of DR prevents visual impairment and blindness. The natural history of DR is that it is asymptomatic until the advanced stages, thus annual retinal examination is recommended for early detection. Previous studies show that the uptake of regular retinal examination among people living with diabetes (PLWD) is low. In the Uptake of Retinal Examination in Diabetes (DURE) study, we will investigate the effectiveness of a complex intervention delivered within diabetes support groups to increase uptake of retinal examination.

Diet may influence vascular function through elevated homocysteine (Hcy) concentrations. However the relationship between dietary patterns (DP), characterised by Hcy and its associated nutrients is unknown.

Motivation improves performance, pushing us beyond our normal limits. One general explanation for this is that the effects of neural noise can be reduced, at a cost. If this were possible, reward would promote investment in resisting noise. But how could the effects of noise be attenuated, and why should this be costly? Negative feedback may be employed to compensate for disturbances in a neural representation. Such feedback would increase the robustness of neural representations to internal signal fluctuations, producing a stable attractor. We propose that encoding this negative feedback in neural signals would incur additional costs proportional to the strength of the feedback signal. We use eye movements to test the hypothesis that motivation by reward improves precision by increasing the strength of internal negative feedback. We find that reward simultaneously increases the amplitude, velocity and endpoint precision of saccades, indicating true improvement in oculomotor performance. Analysis of trajectories demonstrates that variation in the eye position during the course of saccades is predictive of the variation of endpoints, but this relation is reduced by reward. This indicates that motivation permits more aggressive correction of errors during the saccade, so that they no longer affect the endpoint. We suggest that such increases in internal negative feedback allow attractor stability, albeit at a cost, and therefore may explain how motivation improves cognitive as well as motor precision.

Sex differences are widely observed under various circumstances ranging from physiological processes to therapeutic responses, and a myriad of sex-biased genes have been identified. In recent years, transcriptomic datasets of microRNAs (miRNAs), an important class of non-coding RNAs, become increasingly accessible. However, comprehensive analysis of sex difference in miRNA expression has not been performed. Here, we identified the differentially-expressed miRNAs between males and females by examining the transcriptomic datasets available in public databases and conducted a systemic analysis of their biological characteristics. Consequently, we identified 73 female-biased miRNAs (FmiRs) and 163 male-biased miRNAs (MmiRs) across four tissues including brain, colorectal mucosa, peripheral blood, and cord blood. Our results suggest that compared to FmiRs, MmiRs tend to be clustered in the human genome and exhibit higher evolutionary rate, higher expression tissue specificity, and lower disease spectrum width. In addition, functional enrichment analysis of miRNAs show that FmiR genes are significantly associated with metabolism process and cell cycle process, whereas MmiR genes tend to be enriched for functions like histone modification and circadian rhythm. In all, the identification and analysis of sex-biased miRNAs together could provide new insights into the biological differences between females and males and facilitate the exploration of sex-biased disease susceptibility and therapy.

A new family of diphenylpyrimidine derivatives bearing an amino acid substituent were identified as potent BTK inhibitors. Among them, compound 7b, which features an l-proline substituent, was identified as the strongest BTK inhibitor, with an IC50 of 8.7 nM. Compound 7b also displayed similar activity against B-cell lymphoma cell lines as ibrutinib. Moreover, 7b exhibited low cytotoxic activity against normal PBMC cells. In addition, the acridine orange/ethidium bromide (AO/EB) staining assay, Western blot analysis and flow cytometry analysis also showed its effectiveness in interfering with B-cell lymphoma cell growth. The molecular simulation performance showed that 7b forms additional strong hydrogen bonds with the BTK protein. All these findings provided new clues about the pyrimidine scaffold as an effective BTK inhibitor for the treatment of B-cell lymphoma.

The spastin protein (SPAST) contains an ATPase with diverse cellular activities (AAA) domain and regulates microtubule dynamics. Missense mutations of the SPAST gene are frequently detected in patients with hereditary spastic paraplegias (HSPs) and represent the main reason of loss of SPAST function; however, the pathogenicity of mutant SPAST is heterogeneous. Here, SPAST variant with an I344K mutation (I344K-SPAST) was identified in a Korean family with autosomal dominant-type HSP. We investigated the role of the I344K-SPAST in HSP to provide a therapeutic mechanism. The I344K-SPAST mutation prolonged the half-life of the protein compared to wild-type SPAST (WT-SPAST) in cells by modulating post-translational modifications for proteasomal degradation. I344K-SPAST was localized in microtubule but defective in microtubule severing and ATPase activity compared to WT-SPAST in vitro and in cells. Mutant M87 isoform harboring the same mutation with I344K-M1 SPAST also increased protein stability and loss of MT severing activity, but the pathogenicity was not stronger than I344K-M1 SPAST in neurite outgrowth. Overexpression of I344K-SPAST resulted in microtubule accumulation following inhibited neurite growth in neuroblastoma, neural progenitor cells and mouse primary cortical neurons. Conversely, these pathogenic effects of I344K-SPAST were reduced by overexpression of WT-M1 SPAST in a dose dependent manner since WT-SPAST could interact with I344K-SPAST. Our data therefore provide proof-of-concept that gene transfer of WT-M1 SPAST may serve as a valid therapeutic option for HSPs.

Tubulin inhibitors that target the colchicine binding site continue to emerge as promising anticancer agents. In this study, based on the anti-proliferative activities, a novel tubulin inhibitor 7a3 targeting the colchicine binding site was designed, synthesized, and optimized from a series of novel cis-restricted pyrazole analogues of combretastatin A-4. The structure-activity relationships (SARs) of these newly synthesized compounds are summarized indicating that the methyl substituent at the N1 position and deamination were significantly important for the anti-proliferative efficacy. The optimized compound 7a3 exhibited the ability to arrest the cell cycle in the G2/M phase, induce cell apoptosis, and inhibit cell migration in tumour cells. The results of the immunofluorescence analysis using confocal microscopy and the tubulin polymerization assay revealed that tubulin assembly was disrupted by 7a3 in vitro. Furthermore, the targeting identification of 7a3 was illuminated by solving the crystal structure of 7a3 in complex with tubulin at a resolution of 3.2 Å (PDB code 5Z4U), which confirmed the result of molecular docking and further demonstrated that 7a3 binds to the site of colchicine. Moreover, the pharmacokinetic analysis in mouse plasma showed that 7a3 rapidly reached a peak concentration at 0.25 h after intraperitoneal administration, and the T1/2, Cmax, and AUC0-inf were 1.67 ± 0.28 h, 882 ± 71 ng mL-1, and 1166 ± 129 h ng·mL-1, respectively, after a single-dose administration analysed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). In addition, the in vivo study indicated that 7a3 significantly inhibited the tumour growth of the SK-OV-3 xenograft in a nude mouse model. In conclusion, our study proved 7a3 to be a potential microtubule-targeting drug for cancer therapy. The SARs and mechanism of action studies of 7a3 based on the X-ray co-crystal structure provided insights into the next-generation tubulin inhibitors for cancer therapy.

The broad substrate capacity of the intestinal oligopeptide transporter, PepT1, has made it a key target of research into drug delivery. Whilst the substrate capacity of this transporter is broad, studies have largely been limited to small peptides and peptide-like drugs. Here, we demonstrate for the first time that a diverse range of drugs can be targeted towards transport by PepT1 using a hydrolysis resistant carrier. Eleven prodrugs were synthesized by conjugating modified dipeptides containing a thioamide bond to the approved drugs ibuprofen, gabapentin, propofol, aspirin, acyclovir, nabumetone, atenolol, zanamivir, baclofen and mycophenolate. Except for the aspirin and acyclovir prodrugs, which were unstable in the assay conditions and were not further studied, the prodrugs were tested for affinity and transport by PepT1 expressed in Xenopus laevis oocytes: binding affinities ranged from approximately 0.1 to 2 mM. Compounds which showed robust transport in an oocyte trans-stimulation assay were then tested for transcellular transport in Caco-2 cell monolayers: all five tested prodrugs showed significant PepT1-mediated transcellular uptake. Finally, the ibuprofen and propofol prodrugs were tested for absorption in rats: following oral dosing the intact prodrugs and free ibuprofen were measured in the plasma. This provides proof-of-concept for the idea of targeting poorly bioavailable drugs towards PepT1 transport as a general means of improving oral permeability.

Human mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are key enzymes in the mitochondrial protein translation system and catalyze the charging of amino acids on their cognate tRNAs. Mutations in their nuclear genes are associated with pathologies having a broad spectrum of clinical phenotypes, but with no clear molecular mechanism(s). For example, mutations in the nuclear genes encoding mt-AspRS and mt-ArgRS are correlated with the moderate neurodegenerative disorder leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) and with the severe neurodevelopmental disorder pontocerebellar hypoplasia type 6 (PCH6), respectively. Previous studies have shown no or only minor impacts of these mutations on the canonical properties of these enzymes, indicating that the role of the mt-aaRSs in protein synthesis is mostly not affected by these mutations, but their effects on the mitochondrial localizations of aaRSs remain unclear. Here, we demonstrate that three human aaRSs, mt-AspRS, mt-ArgRS, and LysRS, each have a specific sub-mitochondrial distribution, with mt-ArgRS being exclusively localized in the membrane, LysRS exclusively in the soluble fraction, and mt-AspRS being present in both. Chemical treatments revealed that mt-AspRs is anchored in the mitochondrial membrane through electrostatic interactions, whereas mt-ArgRS uses hydrophobic interactions. We also report that novel mutations in mt-AspRS and mt-ArgRS genes from individuals with LBSL and PCH6, respectively, had no significant impact on the mitochondrial localizations of mt-AspRS and mt-ArgRS. The variable sub-mitochondrial locations for these three mt-aaRSs strongly suggest the existence of additional enzyme properties, requiring further investigation to unravel the mechanisms underlying the two neurodegenerative disorders.