Subcellular Ca2+ indicators have yet to be developed for the myofilament where disease mutation or small molecules may alter contractility through myofilament Ca2+ sensitivity. Here, we develop and characterize genetically encoded Ca2+ indicators restricted to the myofilament to directly visualize Ca2+ changes in the sarcomere.

Non-coding RNAs (ncRNAs) are emerging as key regulators and play critical roles in a wide range of tumorigenesis. Recent studies have suggested that long non-coding RNAs (lncRNAs) could interact with microRNAs (miRNAs) and indirectly regulate miRNA targets through competing interactions. Therefore, uncovering the competing endogenous RNA (ceRNA) regulatory mechanism of lncRNAs, miRNAs and mRNAs in post-transcriptional level will aid in deciphering the underlying pathogenesis of human polygenic diseases and may unveil new diagnostic and therapeutic opportunities. However, the functional roles of vast majority of cancer specific ncRNAs and their combinational regulation patterns are still insufficiently understood.

Fruit peel colour is an important agronomic trait for fruit quality. Cytosine methylation plays an important role in gene regulation. Although the DNA methylation level of a single gene is important to affect the phenotype of mutation, there are large unknown of difference of the DNA methylation in plant and its mutants.

Cytochrome P450 (P450) is a functionally diverse and multifamily class of enzymes which catalyses vast variety of biochemical reactions. P450 genes play regulatory role in growth, development and secondary metabolite biosynthesis. Solanum lycopersicum L. (Tomato) is an economically important crop plant and model system for various studies with massive genomic data. The comprehensive identification and characterization of P450 genes was lacking. Probing tomato genome for P450 identification would provide valuable information about the functions and evolution of the P450 gene family.

Maturation of litchi (Litchi chinensis) fruit is characterized by dramatic changes in pigments in the pericarp and flavor compounds in the aril. Among them, the biosynthesis of anthocyanins is most noticeable. Previous studies showed that LcMYB1 and LcbHLH transcription factors participated in regulating the anthocyanin biosynthesis in litchi. However, the roles of other MYB factors remain unclear.

Ultra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs.

Immobilization is an appropriate tool to ease the handling and recycling of enzymes in biocatalytic processes and to increase their stability. Most of the established immobilization methods require case-to-case optimization, which is laborious and time-consuming. Often, (chromatographic) enzyme purification is required and stable immobilization usually includes additional cross-linking or adsorption steps. We have previously shown in a few case studies that the molecular biological fusion of an aggregation-inducing tag to a target protein induces the intracellular formation of protein aggregates, so called inclusion bodies (IBs), which to a certain degree retain their (catalytic) function. This enables the combination of protein production and immobilization in one step. Hence, those biologically-produced immobilizates were named catalytically-active inclusion bodies (CatIBs) or, in case of proteins without catalytic activity, functional IBs (FIBs). While this strategy has been proven successful, the efficiency, the potential for optimization and important CatIB/FIB properties like yield, activity and morphology have not been investigated systematically.

Health-related quality of life (HRQL) in respiratory diseases has been generally investigated in clinical settings, focusing on a single disorder. In this study on a general population sample, we assessed the relationship between HRQL and several respiratory diseases studied simultaneously (COPD, current (CA) and past (PA) asthma, allergic (AR) and non-allergic (NAR) rhinitis and chronic bronchitis (CB).

Serratia plymuthica WS3236 was selected for whole genome sequencing based on preliminary genetic and chemical screening indicating the presence of multiple natural product pathways. This led to the identification of a putative sodorifen biosynthetic gene cluster (BGC). The natural product sodorifen is a volatile organic compound (VOC) with an unusual polymethylated hydrocarbon bicyclic structure (C16H26) produced by selected strains of S. plymuthica. The BGC encoding sodorifen consists of four genes, two of which (sodA, sodB) are homologs of genes encoding enzymes of the non-mevalonate pathway and are thought to enhance the amounts of available farnesyl pyrophosphate (FPP), the precursor of sodorifen. Proceeding from FPP, only two enzymes are necessary to produce sodorifen: an S-adenosyl methionine dependent methyltransferase (SodC) with additional cyclisation activity and a terpene-cyclase (SodD). Previous analysis of S. plymuthica found sodorifen production titers are generally low and vary significantly among different producer strains. This precludes studies on the still elusive biological function of this structurally and biosynthetically fascinating bacterial terpene.

Health-related claims (HRCs) are statements found on food packets that convey the nutritional quality of a food (nutrition claims) and/or its impact on a health outcome (health claims). The EU stated that HRCs should be regulated such that they can only appear on foods that meet a specified nutrient profile (NP). A NP model has been proposed, but not agreed by the European Commission.

Human-assisted reproductive technologies (ART) are a widely accepted treatment for infertile couples. At the same time, many studies have suggested the correlation between ART and increased incidences of normally rare imprinting disorders such as Beckwith-Wiedemann syndrome (BWS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Silver-Russell syndrome (SRS). Major methylation dynamics take place during cell development and the preimplantation stages of embryonic development. ART may prevent the proper erasure, establishment, and maintenance of DNA methylation. However, the causes and ART risk factors for these disorders are not well understood.

Despite the extensive implication of nickel oxide nanoparticles (NiO-NPs) in different fields such as biomedical science and industrial manufacturing, their effect on human cancer cells has not been elucidated. In this study, we report a simple process for the preparation of NiO-NPs. X-ray diffraction and transmission electron microscopy were used to characterize the surface architecture and dimension of the synthesized NiO-NPs. The average diameter of the NiO-NPs was approximately 20-25 nm. We used two human colon cancer cell lines, HT-29 and SW620, to assess the nanoparticles' cytotoxicity. The MTT assay showed that the NiO-NPs reduced cell viability of HT-29 and SW620 cell lines. The results of inverted microscopy showed the highest cytotoxic activity with 600 μg/ml concentration of NiO-NPs on HT-29 cells. Western blot assay showed the downregulation of anti-apoptotic Bcl2 and Bcl-xL proteins in HT-29 cells treated with NiO-NPs. Moreover the results demonstrated the induction of PARP (Cleaved) in NiO-NPs treated HT-29 cells which are considered the marker of apoptosis. The NiO-NPs were not demonstrated bactericidal effect on six different bacterial strains tested, implying that the NiO-NPs may not perturb the human normal gut microbiome. The results have showed the promising application of the NiO-NPs in management of cancer in near future.

Cadmium (Cd) exposure has been associated with an increased risk of cardiovascular diseases. The diet is a modifiable source of protecting or damaging factors that may affect this risk. Herein we tested the hypothesis that a soybean-based diet (SBD) protects the vascular wall of the aorta against Cd-induced pro-inflammatory and pro-apoptotic effects. To test this hypothesis, we fed male Wistar rats for 60 days with a casein-based diet (CBD) or an SBD. These animals were also exposed to tap-water without (CBD-Co/SBD-Co) or with 15(CBD-15Cd/SBD-15Cd) or 100 (CBD-100Cd/SBD-100Cd) ppm of Cd. Inflammatory parameters (mRNAs and/or proteins) were measured in thoracic aorta tissue. These included inducible and endothelial nitric oxide synthases, cyclooxygenase-2, intracellular-adhesion molecule-1, and vascular cell-adhesion molecule-1. As pro-apoptotic parameters, we measured Bax and Bcl-2 mRNA/protein, as well as TUNEL positive cells in the aorta tissue. Compared to CBD-Co, inflammatory and apoptosis markers increased in the aorta with the concentration of Cd in the drinking water. These effects were not observed in either SBD-15Cd or SBD-100Cd, which were similar to CBD-Co. Cd content in serum and in aortas from animals fed CBD-Co/SBD-15Cd or CBD-Co/SBD-100Cd were similar suggesting that, if any, the effect of SBD is not due to changes in Cd bioaccumulation, but due to secondary effects linked to the composition of the dietary soybean flour. Our findings are consistent with a protective effect of an SBD against Cd-induced inflammation and apoptosis in the thoracic aorta in a rat model.

The specific effects of sodium selenite (selenite) on a chemoresistant human bladder cancer cell line RT-112/D21 were investigated during 72 h. Selenite at low concentration of 2.5 μmol (otherwise tolerated in normal urothelial cells UROtsa) suppressed growth and proliferation of the tested cancer cells via induced oxidative stress. Selenite further altered mitochondrial functions (i.e. decreased mitochondrial membrane potential, increased production of superoxide and reduced ATP synthesis), disrupted lysosomal membranes and activated autophagy. These changes in selenite-exposed cells ultimately resulted in their demise via necrosis and other cell death modality displaying heterotypic apoptotic and autophagic features.

It is well known that obesity contributes to the development of systemic inflammatory responses, which in turn may be involved in the process of interstitial fibrosis and left ventricular (LV) remodelling. Activation of pro-inflammatory factors such as transforming growth factor β (TGF-β) can directly stimulate mitogen-activated protein kinase (MAPK) p38 and JNK. The aim of the study was to evaluate the level of TGF-β and MAPK p38 and JNK in the LV in Sprague Dawley (SPRD) rats maintained on a high fat diet (HFD). The SPRD rats from 4 weeks of age were on a normal fat diet (NFD) or a HFD for 12 weeks (NFD-16-week-old rats, NFD 16-wk; or HFD-16-week-old rats, HFD 16-wk) or 16 weeks (NFD-20-week-old rats, NFD 20-wk; or HFD-20-week-old rats, HFD 20-wk). At the end of the experiment, blood and LV were collected from all rats for further analysis (biochemical, Real Time PCR and immunohistochemical analysis). TGF-β mRNA expression did not differ between the study groups of rats. However, p38 MAPK mRNA expression was significantly lower in the HFD 20-wk rats than in both the HFD 16-wk rats and the NFD 20-wk rats. c-jun mRNA expression was significantly higher in the HFD 16-wk rats than in the NFD 16-wk rats. There was significantly lower expression of c-jun mRNA in the HFD 20-wk rats and in the NFD 20-wk rats than in the HFD 16-wk rats and in the NFD 16-wk rats, respectively. TGF-β type II receptor (TβRII) protein demonstrated only cytoplasmic reactivity, while p38 MAPK protein and c-jun protein showed both nuclear and cytoplasmic reactivity. The results suggest that a high fat diet and in two time intervals significantly influence the expression of p38 MAPK and JNK in the LV. However, demonstrating their potential involvement in the processes of interstitial myocardial fibrosis and left ventricular remodeling requires further research.

Twenty-four derivatives structurally related to honokiol have been synthesized and biologically evaluated. IC50 values were determined towards the HT-29, MCF-7 and HEK-293 cell lines. Some of these derivatives exhibited comparable or lower IC50 values than honokiol towards the HT-29 and MCF-7 cell lines or else higher selectivity indexes than the natural product. Twelve selected derivatives were evaluated for their ability to inhibit the expression of the VEGFA, hTERT and c-Myc genes and also to inhibit the production of total c-Myc protein and the secretion of the VEGF protein. One of the most promising compounds, 3-(2,4-dimethoxyphenyl)pyridine, may be a good candidate for further studies as an anticancer agent as it is able to improve the effect shown by honokiol in downregulating all gene expression and protein production at a safe concentration for non-tumor cells.

Mutations in PTEN-induced kinase 1 (PINK1) can cause recessive early-onset Parkinson's disease (PD). Import arrest results in PINK1 kinase activation specifically on damaged mitochondria, triggering Parkin-mediated mitophagy. Here, we show that PINK1 import is less dependent on Tim23 than on mitochondrial membrane potential (ΔΨm). We identified a negatively charged amino acid cluster motif that is evolutionarily conserved just C-terminal to the PINK1 transmembrane. PINK1 that fails to accumulate at the outer mitochondrial membrane, either by mutagenesis of this negatively charged motif or by deletion of Tom7, is imported into depolarized mitochondria and cleaved by the OMA1 protease. Some PD patient mutations also are defective in import arrest and are rescued by the suppression of OMA1, providing a new potential druggable target for PD. These results suggest that ΔΨm loss-dependent PINK1 import arrest does not result solely from Tim23 inactivation but also through an actively regulated "tug of war" between Tom7 and OMA1.

Humans and many animals make frequent saccades requiring coordinated movements of the eyes. When landing on the new fixation point, the eyes must converge accurately or double images will be perceived. We asked whether the visual system uses statistical regularities in the natural environment to aid eye alignment at the end of saccades. We measured the distribution of naturally occurring disparities in different parts of the visual field. The central tendency of the distributions was crossed (nearer than fixation) in the lower field and uncrossed (farther) in the upper field in male and female participants. It was uncrossed in the left and right fields. We also measured horizontal vergence after completion of vertical, horizontal, and oblique saccades. When the eyes first landed near the eccentric target, vergence was quite consistent with the natural-disparity distribution. For example, when making an upward saccade, the eyes diverged to be aligned with the most probable uncrossed disparity in that part of the visual field. Likewise, when making a downward saccade, the eyes converged to enable alignment with crossed disparity in that part of the field. Our results show that rapid binocular eye movements are adapted to the statistics of the 3D environment, minimizing the need for large corrective vergence movements at the end of saccades. The results are relevant to the debate about whether eye movements are derived from separate saccadic and vergence neural commands that control both eyes or from separate monocular commands that control the eyes independently.SIGNIFICANCE STATEMENT We show that the human visual system incorporates statistical regularities in the visual environment to enable efficient binocular eye movements. We define the oculomotor horopter: the surface of 3D positions to which the eyes initially move when stimulated by eccentric targets. The observed movements maximize the probability of accurate fixation as the eyes move from one position to another. This is the first study to show quantitatively that binocular eye movements conform to 3D scene statistics, thereby enabling efficient processing. The results provide greater insight into the neural mechanisms underlying the planning and execution of saccadic eye movements.

Identification of mesial temporal sclerosis is critical in the evaluation of individuals with temporal lobe epilepsy. Our aim was to assess the performance of FDA-approved software measures of hippocampal volume to identify mesial temporal sclerosis in patients with medically refractory temporal lobe epilepsy compared with the initial clinical interpretation of a neuroradiologist.

The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include maximizing response and the use of maintenance therapy. We used whole exome sequencing to study the genetics of paired samples taken at presentation and at relapse from 56 newly diagnosed patients, following induction therapy, randomized to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patients included were considered high risk, relapsing within 30 months of maintenance randomization. Patients achieving a complete response had predominantly branching evolutionary patterns leading to relapse, characterized by a greater mutational burden, an altered mutational profile, bi-allelic inactivation of tumor suppressor genes, and acquired structural aberrations. Conversely, in patients achieving a partial response, the evolutionary features were predominantly stable with a similar mutational and structural profile seen at both time points. There were no significant differences between patients relapsing after lenalidomide maintenance versus observation. This study shows that the depth of response is a key determinant of the evolutionary patterns seen at relapse. This trial is registered at clinicaltrials.gov identifier: 01554852.