The visual word form system in context

According to the “modular” hypothesis, reading is a serial feedforward process, with part of left ventral occipitotemporal cortex the earliest component tuned to familiar orthographic stimuli. Beyond this region, the model predicts no response to arrays of false font in reading-related neural pathways. An alternative “connectionist” hypothesis proposes that reading depends on interactions between feedforward projections from visual cortex and feedback projections from phonological and semantic systems, with no visual component exclusive to orthographic stimuli. This is compatible with automatic processing of false font throughout visual and heteromodal sensory pathways that support reading, in which responses to words may be greater than, but not exclusive of, responses to false font. This functional imaging study investigated these alternative hypotheses by using narrative texts and equivalent arrays of false font and varying the hemifield of presentation using rapid serial visual presentation. The “null” baseline comprised a decision on visually presented numbers. Preferential activity for narratives relative to false font, insensitive to hemifield of presentation, was distributed along the ventral left temporal lobe and along the extent of both superior temporal sulci. Throughout this system, activity during the false font conditions was significantly greater than during the number task, with activity specific to the number task confined to the intraparietal sulci. Therefore, both words and false font are extensively processed along the same temporal neocortical pathways, separate from the more dorsal pathways that process numbers. These results are incompatible with a serial, feedforward model of reading

Molecular insights to the dose-dependent activities of Ashwagandha extracts

Background: Stress is an inevitable component of life. Several herbs are known for their health supporting effects that range from treatment of stress, common cold to cancer. We investigated the dose-dependent effect of Ashwagandha (Withania somnifera) extracts on human normal and cancer cells, and have attempted to resolve the molecular mechanisms of their antistress activities. Methods: Ashwagandha extracts were chemically profiled by HPLC. Cytotoxicity was determined by viability assays. Biochemical and immunoimaging assays were performed using specific antibodies. Results: Human normal cells treated with low doses of the leaf extract or purified withanolides (Withaferin A or Withanone) showed no toxicity. Such non-toxic doses were selected for antistress, neurodifferentiation and neuroregenerative assays. We found that whereas normal cells exposed to oxidative and UV stresses showed poor viability/growth arrest/apoptosis, cells treated with low doses of Ashwagandha extracts were protected. Brain-derived cells exposed to glutamate and scopolamine stresses showed protection and strong differentiation as marked by expression of neurodifferentiation markers. Muscle-derived cells cultured in low doses of extract showed muscle differentiation as marked by expression of muscle differentiation markers. Most recently, using computational tools, we examined potential of Ashwagandha for anti-SARS-CoV2 virus activity, and found that most of the Ashwagandha Withanolides have potential to block cell surface receptors (ACE2 and TMPRSS2) that are involved in entry of virus to human cells. Furthermore, Ashwagandha treated cells showed decrease in ACE2 and TMPRSS2 expression suggesting its potential in blocking virus infection. Conclusion: Ashwagandha extracts and withanolides possess useful bioactivities

Embelin inhibits TNF-α converting enzyme and cancer cell metastasis: molecular dynamics and experimental evidence

BACKGROUND: Embelin, a quinone derivative, is found in the fruits of Embelia ribes Burm (Myrsinaceae). It has been shown to have a variety of therapeutic potentials including anthelmintic, anti-tumor, anti-diabetic, anti-bacterial and anti-inflammation. Inflammation is an immunological response to external harmful stimuli and is regulated by an endogenous pyrogen and pleiotropic pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α). TNF-α production has been implicated in a variety of other human pathologies including neurodegeneration and cancer. Several studies have shown that the anti-inflammatory activity of embelin is mediated by reduction in TNF-α. The latter is synthesized as a membrane anchored protein (pro-TNF-α); the soluble component of pro-TNF-α is then released into the extracellular space by the action of a protease called TNF-α converting enzyme (TACE). TACE, hence, has been proposed as a therapeutic target for inflammation and cancer. METHODS: We used molecular docking and experimental approaches to investigate the docking potential and molecular effects of embelin to TACE and human cancer cell characteristics, respectively. RESULTS: We demonstrate that embelin is a potential inhibitor of TACE. Furthermore, in vitro studies revealed that it inhibits malignant properties of cancer cells through inactivation of metastatic signaling molecules including MMPs, VEGF and hnRNP-K in breast cancer cells. CONCLUSION: Based on the molecular dynamics and experimental data, embelin is proposed as a natural anti-inflammatory and anticancer drug

MortaparibPlus- A Novel Anticancer Small Molecule Abrogating Mortalin-p53 Interaction in Cancer Cells

Background. The cessation of tumor cell growth through cell cycle arrest and apoptosis is determined by p53, a tumor suppressor protein. However, the interaction between mortalin-p53 within cytoplasm/nucleus leads to the inactivation of p53 transcriptional activation function. The disruption of mortalin-p53 complex has been suggested as an approach for developing a potential anticancer drug. Methods. A screening of a high-content chemical library was performed to determine a molecule with mortalin-p53-interaction disrupting characteristics. After four-rounds of visual assays, we discovered a triazole derivative (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole, named MortaparibPlus) with a potential ability of disrupting mortalin-p53-complex. In this study, we recruited two types of cells (different p53 status and point mutation), Colorectal Cancer Cells [HCT116 (p53WT) and DLD-1 (p53 (p53S241F)] and Luminal A Breast Cancer [MCF-7 (p53WT) and T47D (p53L194F)]. We further validated the activity of MortaparibPlus by bioinformatics/experimental analyses. Results. Through bioinformatics analysis, we discovered that MortaparibPlus has potential to block the binding site of mortalin on p53, thus, preventing the formation of mortalin-p53 complex. Immunoprecipitation analyses showed that MortaparibPlus abrogated the mortalin-p53 complex formation and caused growth arrest/apoptosis (via activation of p21WAF1, BAX, and PUMA) in HCT116, DLD-1, and MCF-7 cells. Furthermore, MortaparibPlus posed a cytotoxic effect to cancer cells through various mechanisms (inhibition of PARP1, up-regulation of p73 proteins, downregulation of mortalin and CARF proteins). In contrast, we found that, despite the hyperactivation of PARP1 (PAR accumulation and loss of ATP) as an alternative tumor suppression mechanism, MortaparibPlus-treated T47D cells exhibited signs of neither complete apoptosis nor PAR-Thanatos. Such response was associated with the failure of MortaparibPlus to inhibit the formation of AIF-mortalin complexes. Conclusions. MortaparibPlus is proposed as a potential multimodal small molecule for cancer treatment that requires further extensive laboratory and clinical studies

Comparing the relationship between ultrasound-estimated fetal weight and birthweight in cohort of small for gestational age fetuses

Introduction Small‐for‐gestational‐age (SGA) confers a higher perinatal risk of adverse outcomes. Birthweight cannot be accurately measured until delivery, therefore accurate estimated fetal weight (EFW) based on ultrasonography is important in identifying this high‐risk population. We aimed to establish the sensitivity of detecting SGA infants antenatally in a unit with a selective third‐trimester ultrasound policy and to investigate the association between EFW and birthweight in these babies. Material and methods A retrospective cohort study was conducted on non‐anomalous singleton pregnancies delivered after 36 weeks of gestation where SGA (<10th percentile) was diagnosed at delivery. The EFW at the time of the third‐trimester ultrasound scan was recorded using standard Hadlock formulae. Results In 2017, there were 8392 non‐anomalous singleton pregnancies live born after 36 weeks, excluding late bookers. 797 were live‐born SGA <10th percentile for birthweight and 464 <5th percentile, who met our inclusion criteria. The antenatal detection rate of SGA was 19.6% for babies with birthweight <10th percentile and 24.1% <5th percentile. There was a significant correlation between the EFW and birthweight of fetuses undergoing ultrasound assessment within 2 weeks of delivery (P < .001, r = 0.73 (Pearson correlation). For these cases, EFW was greater than the birthweight in 65% of cases. After adjusting all EFWs using the discrepancy between EFW and actual birthweight for those babies born within 48 hours of the scan, the mean difference between the birthweight and adjusted EFW 7 days before delivery was 111 g (95% CI 87‐136 g) and at 14 days was 200 g (95% CI 153‐248 g). Despite adjusting the EFW, 61/213 cases (28.6%) apparently lost weight between the ultrasound scan and delivery. Conclusions Small‐for‐gestational‐age infants with a birthweight <10th percentile are poorly identified antenatally with little improvement for those <5th percentile. In SGA babies, ultrasound EFW overestimated birthweight. Discrepancies between birthweight and EFW are not explicable only by the limitations of third‐trimester sonography, a reduction in fetal weight close to delivery in a proportion of liveborn SGA babies is plausible

Identification and Characterization of MortaparibPlus—A Novel Triazole Derivative That Targets Mortalin-p53 Interaction and Inhibits Cancer-Cell Proliferation by Wild-Type p53-Dependent and -Independent Mechanisms

p53 has an essential role in suppressing the carcinogenesis process by inducing cell cycle arrest/apoptosis/senescence. Mortalin/GRP75 is a member of the Hsp70 protein family that binds to p53 causing its sequestration in the cell cytoplasm. Hence, p53 cannot translocate to the nucleus to execute its canonical tumour suppression function as a transcription factor. Abrogation of mortalin-p53 interaction and subsequent reactivation of p53’s tumour suppression function has been anticipated as a possible approach in developing a novel cancer therapeutic drug candidate. A chemical library was screened in a high-content screening system to identify potential mortalin-p53 interaction disruptors. By four rounds of visual assays for mortalin and p53, we identified a novel synthetic small-molecule triazole derivative (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole, henceforth named MortaparibPlus). Its activities were validated using multiple bioinformatics and experimental approaches in colorectal cancer cells possessing either wild-type (HCT116) or mutant (DLD-1) p53. Bioinformatics and computational analyses predicted the ability of MortaparibPlus to competitively prevent the interaction of mortalin with p53 as it interacted with the p53 binding site of mortalin. Immunoprecipitation analyses demonstrated the abrogation of mortalin-p53 complex formation in MortaparibPlus-treated cells that showed growth arrest and apoptosis mediated by activation of p21WAF1, or BAX and PUMA signalling, respectively. Furthermore, we demonstrate that MortaparibPlus-induced cytotoxicity to cancer cells is mediated by multiple mechanisms that included the inhibition of PARP1, up-regulation of p73, and also the down-regulation of mortalin and CARF proteins that play critical roles in carcinogenesis. MortaparibPlus is a novel multimodal candidate anticancer drug that warrants further experimental and clinical attention

Resilience and food security: rethinking an ecological concept

1. Focusing on food production, in this paper we define resilience in the food security context as maintaining production of sufficient and nutritious food in the face of chronic and acute environmental perturbations. In agri-food systems, resilience is manifest over multiple spatial scales: field, farm, regional and global. Metrics comprise production and nutritional diversity as well as socio-economic stability of food supply. 2. Approaches to enhancing resilience show a progression from more ecologically-based methods at small scales to more socially-based interventions at larger scales. At the field scale, approaches include the use of mixtures of crop varieties, livestock breeds and of forage species, polycultures, and boosting ecosystem functions. Stress-tolerant crops, or with greater plasticity, provide technological solutions. 3. At the farm scale, resilience may be conferred by diversifying crops and livestock and by farmers implementing adaptive approaches in response to perturbations. Biodiverse landscapes may enhance resilience, but the evidence is weak. At regional to global scales, resilient food systems will be achieved by coordination and implementation of resilience approaches among farms, advice to farmers and targeted research. 4. Synthesis. Threats to food production are predicted to increase under climate change and land degradation. Holistic responses are needed that integrate across spatial scales. Ecological knowledge is critical, but should be implemented alongside agronomic solutions and socio-economic transformations

Mutant p53L194F Harboring Luminal-A Breast Cancer Cells Are Refractory to Apoptosis and Cell Cycle Arrest in Response to MortaparibPlus, a Multimodal Small Molecule Inhibitor

We previously performed a drug screening to identify a potential inhibitor of mortalin–p53 interaction. In four rounds of screenings based on the shift in mortalin immunostaining pattern from perinuclear to pan-cytoplasmic and nuclear enrichment of p53, we had identified MortaparibPlus (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole) as a novel synthetic small molecule. In order to validate its activity and mechanism of action, we recruited Luminal-A breast cancer cells, MCF-7 (p53wild type) and T47D (p53L194F) and performed extensive biochemical and immunocytochemical analyses. Molecular analyses revealed that MortaparibPlus is capable of abrogating mortalin–p53 interaction in both MCF-7 and T47D cells. Intriguingly, upregulation of transcriptional activation function of p53 (as marked by upregulation of the p53 effector gene—p21WAF1—responsible for cell cycle arrest and apoptosis) was recorded only in MortaparibPlus-treated MCF-7 cells. On the other hand, MortaparibPlus-treated T47D cells exhibited hyperactivation of PARP1 (accumulation of PAR polymer and decrease in ATP levels) as a possible non-p53 tumor suppression program. However, these cells did not show full signs of either apoptosis or PAR-Thanatos. Molecular analyses attributed such a response to the inability of MortaparibPlus to disrupt the AIF–mortalin complexes; hence, AIF did not translocate to the nucleus to induce chromatinolysis and DNA degradation. These data suggested that the cancer cells possessing enriched levels of such complexes may not respond to MortaparibPlus. Taken together, we report the multimodal anticancer potential of MortaparibPlus that warrants further attention in laboratory and clinical studies