RELATIONSHIP BETWEEN CRANIAL BASE DEVELOPMENT AND CLEFT LIP AND PALATE IN PRICKLE1 BEETLEJUICE MUTANT: CASE CONTROL STUDY

Cleft lip and/or palate (CL/P) is one of the most common congenital anomalies in United States. Its etiology is complex, multifactorial, and not well understood. This study focuses on Prickle1 Beetlejuice (BJ) mutants which tend to have compressed and wide facial morphology. Prickle1 is a core component of Wnt/Planar cell polarity(PCP) pathway and the Prickle1Bj mouse line has a missense mutation (p.Cys161Phe) that disrupts the LIM1 domain in Prickle1. These mutants have approximately 50% chance of developing a cleft palate. Because cranial base size and shape determine the perimeter of growth for the lower 2/3 of the face, we examine the association between cranial base development and orofacial cleft. We found that Prickle1Bj/Bj with cleft lip and/or palate have wider, shorter, and less dense basisphenoid compared to wild type. Mutants with both cleft lip and palate compared to mutants with cleft lip only have even shorter and less dense basisphenoid. However, the basisphenoid width difference between the mutant groups was not statistically significant. Our data supports the conclusion that wide basal cranium poses higher risk of developing orofacial cleft. Yet, basisphenoid bone density is the superior value in determining the degree of orofacial cleft

Suppression of the Hepatitis C viral load by Phyllanthus niruri extracts

Gemstone Team ANTIDOTEHepatitis C virus (HCV) is a public health crisis, affecting over 170 million people by 2011. Conventional treatment, interferon alpha with ribavirin, can often be ineffective and may lead to severe side effects, and this lack of effective treatment poses significant challenges to patients, healthcare providers, and public health officials. As a result, our team investigated the therapeutic potential of medicinal plant extracts from Phyllanthus niruri as an alternative treatment for HCV. Molecular barcoding of chloroplast genes rbcl and matk was used to document the genetic identity of our plants. Phytochemicals were then extracted from dried plant material to isolate potential active compounds. We applied the extraction products to HCV-infected cell lines, specifically Huh7.5 liver cancer cells with J6JFH virus, to determine their effects on viral load and cell toxicity. Our extracts significantly decrease the number of viral copies per cell with no significant toxicity. Viral load suppression was strongest 24 hours after treatment. This effect either declined (extracts 3 and 4) or was sustained (extracts 1 and 2) over time. Extract 4 at 1 μg/ml at 24 hours and 5 at 10 μg/ml at 96 hours reached near 100% suppression, demonstrating significant potent effect comparable to interferon-alpha, but the effect of Extract 4 is not sustained. It also demonstrates different extracts may exhibit different kinetics, suggesting different mechanisms of action. Overall, our study serves as a building block to develop novel treatments and contributes to the discovery of alternative drug options for HCV patients

NeurIPS 2020 EfficientQA Competition: Systems, Analyses and Lessons Learned

We review the EfficientQA competition from NeurIPS 2020. The competition focused on open-domain question answering (QA), where systems take natural language questions as input and return natural language answers. The aim of the competition was to build systems that can predict correct answers while also satisfying strict on-disk memory budgets. These memory budgets were designed to encourage contestants to explore the trade-off between storing retrieval corpora or the parameters of learned models. In this report, we describe the motivation and organization of the competition, review the best submissions, and analyze system predictions to inform a discussion of evaluation for open-domain QA

How does the time frame imposed by tourist travel on customers, impact on salespeople’s perceptions and the experience of ‘luxury’ at Bicester Village?

Purpose – The main aim of this research is to examine the perception of salespeople towards luxury brands in an outlet context and detail their attempts to implement a luxury experience when hurried tourist customers face a tight timeframe. Design / Methodology / Approach – By conducting an inductive approach, this research will utilise a strategy of qualitative research though in-depth interviews. For the questions, a semi-structured interview format was chosen to collect the data. The questions were based on Bakker and Demerouti’s (2007) Job Resource-Demand model. All respondents are salespeople who work for luxury brand outlets in Bicester Village. The data was collected in 2018 and 2019. Findings – The results indicate that salespeople who work in outlet luxury brands are generally aware that they work in the luxury field. However, when their customers are hurried, salespeople become stressed as delivering a luxury experience in a tight timeframe is almost paradoxical. This causes a negative perception towards the luxury brands that they work for. Practical implication – The results are helpful as they identify; what perception salespeople have towards luxury brands, why luxury experience is significant to luxury brands and how a luxury experience can be implemented in an outlet context. This information will provide a guideline for; luxury brands looking to further develop a particular outlet business strategy, those marketing a luxury experience to outlet customers and academics within the marketing field. Originality / Value – This research is the first to explore and examine the perception of luxury fashion brands from the perspective of salespeople in an outlet context, where hurried customers are the norm. As there is no previous study of salespeople who work in an outlet, the main contribution of this paper consists of its examination of the link between luxury perception and outlet shopping. Also, this study deals with the difference between the delivery of a luxury experience in a luxury fashion main boutique store and an outlet store

Development of 5-Fluorouracil/pH-Responsive Adjuvant-Embedded Extracellular Vesicles for Targeting α_vβ₃ Integrin Receptors in Tumors

To selectively target and treat murine melanoma B16BL6 tumors expressing αvβ3 integrin receptors, we engineered tumor-specific functional extracellular vesicles (EVs) tailored for the targeted delivery of antitumor drugs. This objective was achieved through the incorporation of a pH-responsive adjuvant, cyclic arginine-glycine-aspartic acid peptide (cRGD, serving as a tumor-targeting ligand), and 5-fluorouracil (5-FU, employed as a model antitumor drug). The pH-responsive adjuvant, essential for modulating drug release, was synthesized by chemically conjugating 3-(diethylamino)propylamine (DEAP) to deoxycholic acid (DOCA, a lipophilic substance capable of integrating into EVs’ membranes), denoted as DEAP-DOCA. The DOCA, preactivated using N-(2-aminoethyl)maleimide (AEM), was chemically coupled with the thiol group of the cRGD-DOCA through the thiol–maleimide click reaction, resulting in the formation of cRGD-DOCA. Subsequently, DEAP-DOCA, cRGD-DOCA, and 5-FU were efficiently incorporated into EVs using a sonication method. The resulting tumor-targeting EVs, expressing cRGD ligands, demonstrated enhanced in vitro/in vivo cellular uptake specifically for B16BL6 tumors expressing αvβ3 integrin receptors. The ionization characteristics of the DEAP in DEAP-DOCA induced destabilization of the EVs membrane at pH 6.5 through protonation of the DEAP substance, thereby expediting 5-FU release. Consequently, an improvement in the in vivo antitumor efficacy was observed for B16BL6 tumors. Based on these comprehensive in vitro/in vivo findings, we anticipate that this EV system holds substantial promise as an exceptionally effective platform for antitumor therapeutic delivery

Prediction of gastric pH‐mediated drug exposure using physiologically‐based pharmacokinetic modeling: A case study of itraconazole

Abstract Abnormal gastric acidity, including achlorhydria, can act as a significant source of variability in orally administered drugs especially with pH‐sensitive solubility profiles, such as weak bases, potentially resulting in an undesirable therapeutic response. This study aimed to evaluate the utility of physiologically‐based pharmacokinetic (PBPK) modeling in the prediction of gastric pH‐mediated drug exposure by using itraconazole, a weak base, as a case. An itraconazole PBPK model was developed on the mechanistic basis of its absorption kinetics in a middle‐out manner from a stepwise in vitro‐in vivo extrapolation to in vivo refinement. Afterward, an independent prospective clinical study evaluating gastric pH and itraconazole pharmacokinetics (PKs) under normal gastric acidity and esomeprazole‐induced gastric hypoacidity was conducted for model validation. Validation was performed by comparing the predicted data with the clinical observations, and the valid model was subsequently applied to predict PK changes under achlorhydria. The developed itraconazole PBPK model showed reasonable reproducibility for gastric pH‐mediated exposure observed in the clinical investigation. Based on the model‐based simulations, itraconazole exposure was expected to be decreased up to 65% under achlorhydria, and furthermore, gastric pH‐mediated exposure could be mechanistically interpreted according to sequential variation in total solubility, dissolution, and absorption. This study suggested the utility of PBPK modeling in the prediction of gastric pH‐mediated exposure, especially for drugs whose absorption is susceptible to gastric pH. Our findings will serve as a leading model for further mechanistic assessment of exposure depending on gastric pH for various drugs, ultimately contributing to personalized pharmacotherapy

Alendronate/cRGD-Decorated Ultrafine Hyaluronate Dot Targeting Bone Metastasis

In this study, we report the hyaluronate dot (dHA) with multiligand targeting ability and a photosensitizing antitumor model drug for treating metastatic bone tumors. Here, the dHA was chemically conjugated with alendronate (ALN, as a specific ligand to bone), cyclic arginine-glycine-aspartic acid (cRGD, as a specific ligand to tumor integrin αvβ3), and photosensitizing chlorin e6 (Ce6, for photodynamic tumor therapy), denoted as (ALN/cRGD)@dHA-Ce6. These dots thus prepared (≈10 nm in diameter) enabled extensive cellular interactions such as hyaluronate (HA)-mediated CD44 receptor binding, ALN-mediated bone targeting, and cRGD-mediated tumor integrin αvβ3 binding, thus improving their tumor targeting efficiency, especially for metastasized MDA-MB-231 tumors. As a result, these dots improved the tumor targeting efficiency and tumor cell permeability in a metastatic in vivo tumor model. Indeed, we demonstrated that (ALN/cRGD)@dHA-Ce6 considerably increased photodynamic tumor ablation, the extent of which is superior to that of the tumor ablation of dot systems with single or double ligands. These results indicate that dHA with multiligand can provide an effective treatment strategy for metastatic bone tumors

Simultaneous surface modification method for 0.4Li2MnO3-0.6LiNi1/3Co1/3Mn1/3O2 cathode material for lithium ion batteries: Acid treatment and LiCoPO4 coating

Li-rich layered cathode materials have been considered the most promising candidates for large-scale Li-ion batteries due to their low cost and high reversible capacity. However, these materials have many drawbacks that hinder commercialization, such as low initial efficiency and cyclability at elevated temperatures. To overcome these barriers, we propose an efficient and effective surface modification method, in which chemical activation (acid treatment) and LiCoPO4 coating were carried out simultaneously. During the synthesis, the lithium ions were extracted from the lattice, leading to improved Columbic efficiency, and these ions were used for the formation of LiCoPO4. The Ni and Co doped spinel phase was formed at the surface of the host material, which gives rise to the facile pathway for lithium ions. The LiCoPO4 and highly doped spinel on the surface acted as double protection layers that effectively prevented side reactions on the surface at 60 ??C. Moreover, the transition metal migration of the modified cathode was weakened, due to the presence of the spinel structure at the surface. Consequently, the newly developed Li-rich cathode material exhibited a high 1st efficiency of 94%, improved capacity retention of 82% during 100 cycles at 60 ??C, and superior rate capability of 62% at 12C (1C = 200 mA/g) rate at 24 ??C. In addition, the thermal stability of the modified cathode was significantly improved as compared to that of a bare counterpart at 4.6 V, showing a 60% decrease in the total heat generation