Miracle-dz/UniFAR-FTUs huggingface dataset:
APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma

Objectives p53 is a critical tumour suppressor and is mutated in 70% of oesophageal adenocarcinomas (OACs), resulting in chemoresistance and poor survival. APR-246 is a first-in-class reactivator of mutant p53 and is currently in clinical trials. In this study, we characterised the activity of APR-246 and its effect on p53 signalling in a large panel of cell line xenograft (CLX) and patient-derived xenograft (PDX) models of OAC. Design In vitro response to APR-246 was assessed using clonogenic survival, cell cycle and apoptosis assays. Ectopic expression, gene knockdown and CRISPR/Cas9-mediated knockout studies of mutant p53 were performed to investigate p53-dependent drug effects. p53 signalling was examined using quantitative RT-PCR and western blot. Synergistic interactions between APR-246 and conventional chemotherapies were evaluated in vitro and in vivo using CLX and PDX models. Results APR-246 upregulated p53 target genes, inhibited clonogenic survival and induced cell cycle arrest as well as apoptosis in OAC cells harbouring p53 mutations. Sensitivity to APR-246 correlated with cellular levels of mutant p53 protein. Ectopic expression of mutant p53 sensitised p53-null cells to APR-246, while p53 gene knockdown and knockout diminished drug activity. Importantly, APR-246 synergistically enhanced the inhibitory effects of cisplatin and 5-fluorouracil through p53 accumulation. Finally, APR-246 demonstrated potent antitumour activity in CLX and PDX models, and restored chemosensitivity to a cisplatin/5-fluorouracil-resistant xenograft model. Conclusions APR-246 has significant antitumour activity in OAC. Given that APR-246 is safe at therapeutic levels our study strongly suggests that APR-246 can be translated into improving the clinical outcomes for OAC patients.
Motivators and Barriers for Physical Activity in Older Adults With Osteoporosis

Background and Purpose:Although physical activity (PA) is an important tool to counter osteoporosis, too few older patients with osteoporosis (OPWO) engage in PA. Little is known about specific motivators for and barriers to PA in OPWO, hindering the development of targeted PA promotion campaigns for these persons. Therefore, the main objective of this study was to identify motivators for and barriers to PA specifically in OPWO. Methods:This qualitative study identified specific motivators for and barriers to PA in OPWO through 2 different methods: focus groups with professionals and in-depth interviews with OPWO. Results:The OPWO tended to give a broad interpretation of what they considered as PA (practicing sports, physical work, and performing household activities), whereas the professionals seemed to mainly focus on (therapeutic) exercise as PA. Fifteen different motivators and 18 barriers have been identified. Among others, health improvement, social contact, habit, feeling good, and receiving medical advice from a medical doctor were motivators. Pain, fear of falling, bad weather, lack of interest, and caring for an ill partner were barriers to PA. For some older respondents, osteoporosis acted as a trigger for PA, and for others it was a barrier. Conclusions:This study emphasizes the importance for health care professionals to give personalized PA advice regarding the nature and frequency of PA that is safe and beneficial for osteoporosis. It stands to reason that the information about PA needs to be clear and consistent. Furthermore, it is quintessential to mention that it can take some time to adapt to physical exercise and to experience the beneficial effects, because pain sensations during the first PA sessions can be perceived as barriers to OPWO. Misconceptions or barriers to PA should be countered by assessing motivators for and barriers to PA by the health care professional together with the older client so that barriers can be eliminated and motivators can be strengthened. Physical activity education should involve not only the OPWO but also their relatives, friends, and important peers. Different social aspects of PA and the encouragements from peers are stimulating for older adults to initiate and to continue PA. The results of our study can constitute a starting point for further research to identify the motivators for and barriers to PA with the highest impact on PA behavior in OPWO, thus enabling evidence-based PA promotion campaigns for this patient group.
Influence of respiratory function parameters on the quality of life of COPD patients.

OBJECTIVE To determine the quality of life of COPD patients by using the Medical Outcomes 36-item Short-Form Survey (SF-36) and the Saint George's Respiratory Questionnaire (SGRQ), correlating the scores with respiratory function parameters. METHODS This was a cross-sectional study involving 42 COPD patients. We used the SGRQ (a specific questionnaire) and the SF-36 (a general questionnaire), together with their component summaries, in order to determine the quality of life of these patients. The functional profile was assessed by means of spirometry, arterial blood gas analysis and the six-minute walk test. RESULTS Of the 42 patients, 30 (71.4%) were male and 12 (28.6%) were female. The mean age of the patients was 65.4 +/- 8.0 years. The mean physical component summary and mean mental component summary scores were 37.05 +/- 11.19 and 45.61 +/- 15.65, respectively. The physical component summary correlated significantly with FEV(1) in L/s (r = 0.38; p = 0.012). There was a correlation between the SGRQ total score and FEV(1) (r = -0.50; p < 0.01). The SGRQ activity domain showed negative correlations with all respiratory function parameters. The multiple regression analysis showed that only FEV(1) correlated significantly with the SGRQ total score, as well as with the activity domain score (r= -0.32; p = 0.04 and r = -0.34; p = 0.03, respectively). CONCLUSIONS In COPD patients, a decline in FEV(1) is associated with poorer quality of life, as evaluated using the SGRQ.
Relation Between Serum Phosphate Level and Cardiovascular Event Rate in People With Coronary Disease

Background— Higher levels of serum phosphate are associated with adverse cardiovascular outcomes, especially in the setting of overt hyperphosphatemia. Given the biological importance of phosphorus, it is plausible that higher levels of serum phosphate within the normal range may also be associated with adverse outcomes. Methods and Results— We performed a post hoc analysis of data from the Cholesterol And Recurrent Events (CARE) study. Baseline serum phosphate levels were measured in 4127 fasting participants who were randomized to receive pravastatin 40 mg daily or placebo and followed up for a median of 59.7 months. We used Cox proportional-hazards models to examine the association between serum phosphate and adverse clinical outcomes after adjustment for potential confounders. During nearly 60 months of follow-up, 375 participants died. A significant association was noted between baseline serum phosphate level and the age-, race-, and sex-adjusted risk of all-cause death (hazard ratio per 1 mg/dL, 1.27; 95% confidence interval, 1.02 to 1.58). After categorization based on baseline phosphate level (<2.5, 2.5 to 3.4, 3.5 to 3.9, and ≥4 mg/dL) and further adjustment, a graded independent relation between phosphate and death was observed (P for trend=0.03). For instance, participants with serum phosphate ≥3.5 mg/dL had an adjusted hazard ratio for death of 1.27 (95% confidence interval, 1.02 to 1.59) compared with those with serum phosphate of <3.5 mg/dL. Higher levels of serum phosphate were also associated with increased risk of new heart failure, myocardial infarction, and the composite of coronary death or nonfatal myocardial infarction, but not the risk of stroke. Conclusions— We found a graded independent relation between higher levels of serum phosphate and the risk of death and cardiovascular events in people with prior myocardial infarction, most of whom had serum phosphate levels within the normal range. Given the ready availability and low cost of serum phosphate assays, this finding may prove clinically useful.
The EBV Immunoevasins vIL-10 and BNLF2a Protect Newly Infected B Cells from Immune Recognition and Elimination

Lifelong persistence of Epstein-Barr virus (EBV) in infected hosts is mainly owed to the virus' pronounced abilities to evade immune responses of its human host. Active immune evasion mechanisms reduce the immunogenicity of infected cells and are known to be of major importance during lytic infection. The EBV genes BCRF1 and BNLF2a encode the viral homologue of IL-10 (vIL-10) and an inhibitor of the transporter associated with antigen processing (TAP), respectively. Both are known immunoevasins in EBV's lytic phase. Here we describe that BCRF1 and BNLF2a are functionally expressed instantly upon infection of primary B cells. Using EBV mutants deficient in BCRF1 and BNLF2a, we show that both factors contribute to evading EBV-specific immune responses during the earliest phase of infection. vIL-10 impairs NK cell mediated killing of infected B cells, interferes with CD4+ T-cell activity, and modulates cytokine responses, while BNLF2a reduces antigen presentation and recognition of newly infected cells by EBV-specific CD8+ T cells. Together, both factors significantly diminish the immunogenicity of EBV-infected cells during the initial, pre-latent phase of infection and may improve the establishment of a latent EBV infection in vivo.
Molecular Switches at the Synapse Emerge from Receptor and Kinase Traffic

Changes in the synaptic connection strengths between neurons are believed to play a role in memory formation. An important mechanism for changing synaptic strength is through movement of neurotransmitter receptors and regulatory proteins to and from the synapse. Several activity-triggered biochemical events control these movements. Here we use computer models to explore how these putative memory-related changes can be stabilised long after the initial trigger, and beyond the lifetime of synaptic molecules. We base our models on published biochemical data and experiments on the activity-dependent movement of a glutamate receptor, AMPAR, and a calcium-dependent kinase, CaMKII. We find that both of these molecules participate in distinct bistable switches. These simulated switches are effective for long periods despite molecular turnover and biochemical fluctuations arising from the small numbers of molecules in the synapse. The AMPAR switch arises from a novel self-recruitment process where the presence of sufficient receptors biases the receptor movement cycle to insert still more receptors into the synapse. The CaMKII switch arises from autophosphorylation of the kinase. The switches may function in a tightly coupled manner, or relatively independently. The latter case leads to multiple stable states of the synapse. We propose that similar self-recruitment cycles may be important for maintaining levels of many molecules that undergo regulated movement, and that these may lead to combinatorial possible stable states of systems like the synapse.
Super-resolution Person re-identification with semi-coupled low-rank discriminant dictionary learning

Person re-identification has been widely studied due to its importance in surveillance and forensics applications. In practice, gallery images are high-resolution (HR) while probe images are usually low-resolution (LR) in the identification scenarios with large variation of illumination, weather or quality of cameras. Person re-identification in this kind of scenarios, which we call super-resolution (SR) person re-identification, has not been well studied. In this paper, we propose a semi-coupled low-rank discriminant dictionary learning (SLD2L) approach for SR person re-identification. For the given training image set which consists of HR gallery and LR probe images, we aim to convert the features of LR images into discriminating HR features. Specifically, our approach learns a pair of HR and LR dictionaries and a mapping from the features of HR gallery images and LR probe images. To ensure that the converted features using the learned dictionaries and mapping have favorable discriminative capability, we design a discriminant term which requires the converted HR features of LR probe images should be close to the features of HR gallery images from the same person, but far away from the features of HR gallery images from different persons. In addition, we apply low-rank regularization in dictionary learning procedure such that the learned dictionaries can well characterize intrinsic feature space of HR and LR images. Experimental results on public datasets demonstrate the effectiveness of SLD2L.
Endothelium Trans Differentiated from Wharton's Jelly Mesenchymal Cells Promote Tissue Regeneration: Potential Role of Soluble Pro-Angiogenic Factors

Background Mesenchymal stem cells have a high capacity for trans-differentiation toward many adult cell types, including endothelial cells. Feto-placental tissue, such as Wharton's jelly is a potential source of mesenchymal stem cells with low immunogenic capacity; make them an excellent source of progenitor cells with a potential use for tissue repair. We evaluated whether administration of endothelial cells derived from mesenchymal stem cells isolated from Wharton's jelly (hWMSCs) can accelerate tissue repair in vivo. Methods Mesenchymal stem cells were isolated from human Wharton's jelly by digestion with collagenase type I. Endothelial trans-differentiation was induced for 14 (hWMSC-End14d) and 30 (hWMSC-End30d) days. Cell phenotyping was performed using mesenchymal (CD90, CD73, CD105) and endothelial (Tie-2, KDR, eNOS, ICAM-1) markers. Endothelial trans-differentiation was demonstrated by the expression of endothelial markers and their ability to synthesize nitric oxide (NO). Results hWMSCs can be differentiated into adipocytes, osteocytes, chondrocytes and endothelial cells. Moreover, these cells show high expression of CD73, CD90 and CD105 but low expression of endothelial markers prior to differentiation. hWMSCs-End express high levels of endothelial markers at 14 and 30 days of culture, and also they can synthesize NO. Injection of hWMSC-End30d in a mouse model of skin injury significantly accelerated wound healing compared with animals injected with undifferentiated hWMSC or injected with vehicle alone. These effects were also observed in animals that received conditioned media from hWMSC-End30d cultures. Conclusion These results demonstrate that mesenchymal stem cells isolated from Wharton's jelly can be cultured in vitro and trans-differentiated into endothelial cells. Differentiated hWMSC-End may promote neovascularization and tissue repair in vivo through the secretion of soluble pro-angiogenic factors.
Endothelial cell serine proteases expressed during vascular morphogenesis and angiogenesis

Summary Many serine proteases play important regulatory roles in complex biological systems, but only a few have been linked directly with capillary morphogenesis and angiogenesis. Here we provide evidence that serine protease activities, independent of the plasminogen activation cascade, are required for microvascular endothelial cell reorganization and capillary morphogenesis in vitro. A homology cloning approach targeting conserved motifs present in all serine proteases, was used to identify candidate serine proteases involved in these processes, and revealed 5 genes (acrosin, testisin, neurosin, PSP and neurotrypsin), none of which had been associated previously with expression in endothelial cells. A subsequent gene-specific RT-PCR screen for 22 serine proteases confirmed expression of these 5 genes and identified 7 additional serine protease genes expressed by human endothelial cells, urokinase-type plasminogen activator, protein C, TMPRSS2, hepsin, matriptase/ MT-SP1, dipeptidylpeptidase IV, and seprase. Differences in serine protease gene expression between microvascular and human umbilical vein endothelial cells (HUVECs) were identified and several serine protease genes were found to be regulated by the nature of the substratum, ie. artificial basement membrane or fibrillar type I collagen. mRNA transcripts of several serine protease genes were associated with blood vessels in vivo by in situ hybridization of human tissue specimens. These data suggest a potential role for serine proteases, not previously associated with endothelium, in vascular function and angiogenesis.
Assessment of Blood Glucose Regulation and Safety of Resistant Starch Formula-Based Diet in Healthy Normal and Subjects With Type 2 Diabetes

Abstract To evaluate the effects of the new resistant starch (RS) formula, PPB-R-203, on glucose homeostasis in healthy subjects and subjects with type 2 diabetes.A cohort consisting of 40 healthy participants received test and control diets and was checked for up to 3 hours post-meal. A randomized, 2-regimen, cross-over, comparative study was conducted in 44 subjects with type 2 diabetes and glycemic control was assessed with a continuous glucose monitoring system.In healthy participants, serum glucose values and incremental areas under the glucose curves (AUC) were significantly lower in the PPB-R-203 than the control group (P < 0.05). In patients with type 2 diabetes, mean blood glucose concentrations for subjects on the control regimen were higher than those for subjects on the PPB-R-203-based regimen (7.9 ± 1.7, 95% confidence interval [CI] 7.4–8.4 vs 7.4 ± 1.6, 95% CI 6.9–7.9 mmol/L, respectively; P = 0.023). AUCs for total blood glucose and hyperglycemia (glucose >10 mmol/L) were also reduced for subjects on the PPB-R-203-based regimen as compared with those on control regimen (total blood glucose: 16.2 ± 4.0, 95% CI 14.9–17.4 vs 18.7 ± 4.0, 95% CI 17.6–20.1, P < 0.001; hyperglycemia: 4.9 ± 5.7, 95% CI 3.1–6.6 vs 6.3 ± 6.4, 95% CI 4.3–8.3 mmol/L × day, P = 0.021). However, AUC measurements for hypoglycemia (glucose <3.9 mmol/l) were not statistically significant.A PPB-R-203-based diet reduced postprandial hyperglycemia in patients with type 2 diabetes without increasing the risk of hypoglycemia or glucose excursion.
How Clonal Is Clonal? Genome Plasticity across Multicellular Segments of a “Candidatus Marithrix sp.” Filament from Sulfidic, Briny Seafloor Sediments in the Gulf of Mexico

“Candidatus Marithrix” is a recently described lineage within the group of large sulfur bacteria (Beggiatoaceae, Gammaproteobacteria). This genus of bacteria comprises vacuolated, attached-living filaments that inhabit the sediment surface around vent and seep sites in the marine environment. A single filament is ca. 100 μm in diameter, several millimeters long, and consists of hundreds of clonal cells, which are considered highly polyploid. Based on these characteristics, “Candidatus Marithrix” was used as a model organism for the assessment of genomic plasticity along segments of a single filament using next generation sequencing to possibly identify hotspots of microevolution. Using six consecutive segments of a single filament sampled from a mud volcano in the Gulf of Mexico, we recovered ca. 90% of the “Candidatus Marithrix” genome in each segment. There was a high level of genome conservation along the filament with average nucleotide identities between 99.98 and 100%. Different approaches to assemble all reads into a complete consensus genome could not fill the gaps. Each of the six segment datasets encoded merely a few hundred unique nucleotides and 5 or less unique genes—the residual content was redundant in all datasets. Besides the overall high genomic identity, we identified a similar number of single nucleotide polymorphisms (SNPs) between the clonal segments, which are comparable to numbers reported for other clonal organisms. An increase of SNPs with greater distance of filament segments was not observed. The polyploidy of the cells was apparent when analyzing the heterogeneity of reads within a segment. Here, a strong increase in single nucleotide variants, or “intrasegmental sequence heterogeneity” (ISH) events, was observed. These sites may represent hotspots for genome plasticity, and possibly microevolution, since two thirds of these variants were not co-localized across the genome copies of the multicellular filament.
Hold‐Up: With a Vengeance

When contracts are incomplete or unenforceable, inefficient levels of investment may occur because of hold-up. If individuals care for negative reciprocity, these problems may be reduced, as revenge becomes a credible threat. However, negative reciprocity has this effect only when the investor holds the rights of control of the investment proceeds. We explore this issue analytically, deriving predictions for hold-up games which differ as regards assignment of rights of control. We also test and support these predictions in an experiment.
Structural basis for the cooperative DNA recognition by Smad4 MH1 dimers

Smad proteins form multimeric complexes consisting of the ‘common partner’ Smad4 and receptor regulated R-Smads on clustered DNA binding sites. Deciphering how pathway specific Smad complexes multimerize on DNA to regulate gene expression is critical for a better understanding of the cis-regulatory logic of TGF-β and BMP signaling. To this end, we solved the crystal structure of the dimeric Smad4 MH1 domain bound to a palindromic Smad binding element. Surprisingly, the Smad4 MH1 forms a constitutive dimer on the SBE DNA without exhibiting any direct protein–protein interactions suggesting a DNA mediated indirect readout mechanism. However, the R-Smads Smad1, Smad2 and Smad3 homodimerize with substantially decreased efficiency despite pronounced structural similarities to Smad4. Therefore, intricate variations in the DNA structure induced by different Smads and/or variant energetic profiles likely contribute to their propensity to dimerize on DNA. Indeed, competitive binding assays revealed that the Smad4/R-Smad heterodimers predominate under equilibrium conditions while R-Smad homodimers are least favored. Together, we present the structural basis for DNA recognition by Smad4 and demonstrate that Smad4 constitutively homo- and heterodimerizes on DNA in contrast to its R-Smad partner proteins by a mechanism independent of direct protein contacts.
AIS Electronic Library (AISeL)

The aim of this study is to identify the factors that influence the assimilation of enterprise resource planning (ERP) systems in the post-implementation stage. Building on organizational information processing theory (OIPT) and absorptive capacity (AC), we propose an integrated model, which examines the relationship among organizational fit, absorptive capacity, environmental uncertainty, and ERP assimilation. Based on the survey data from 98 firms that have implemented ERP, most of the proposed hypotheses were supported, showing that initial fit, potential AC, realized AC, and heterogeneity jointly affect ERP assimilation. Task uncertainty (hostility and heterogeneity) negatively moderates the relationship between initial fit and ERP assimilation. The implications for both theory and practice are discussed.
A Comparative Study of the Effect of Different Converter Topologies on the Iron Loss of Nonoriented Electrical Steel

In this paper, a comparative study of the effect of different converter topologies on the iron loss of nonoriented electrical steel is presented. Three converter topologies are considered in this investigation; namely: two-, three-, and five-level power converters. Moreover, the effect of the carrier frequency on both the iron loss and converter loss is introduced. The experimental results show a dramatic increase of the iron loss for the two-level converter, especially for low levels of the carrier frequency. Furthermore, the increase of the iron loss is negligible for the multilevel converter topologies. Specifically, the use of the five-level converter, even at a low value of the carrier frequency, results in lower iron losses than the three-level converter at a relatively higher carrier frequency.