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Nanocrystals offer a unique platform for tailoring the physicochemical properties of solid materials to enhance their performances in various applications. While most work on controlling their shapes revolves around symmetrical growth, the introduction of asymmetrical growth and thus symmetry breaking has also emerged as a powerful route to enrich metal nanocrystals with new shapes and complex morphologies as well as unprecedented properties and functionalities. The success of this route critically relies on our ability to lift the confinement on symmetry by the underlying unit cell of the crystal structure and/or the initial seed in a systematic manner. This Review aims to provide an account of recent progress in understanding and controlling asymmetrical growth and symmetry breaking in a colloidal synthesis of noble-metal nanocrystals. With a touch on both the nucleation and growth steps, we discuss a number of methods capable of generating seeds with diverse symmetry while achieving asymmetrical growth for mono-, bi-, and multimetallic systems. We then showcase a variety of symmetry-broken nanocrystals that have been reported, together with insights into their growth mechanisms. We also highlight their properties and applications and conclude with perspectives on future directions in developing this class of nanomaterials. It is hoped that the concepts and existing challenges outlined in this Review will drive further research into understanding and controlling the symmetry breaking process.

Purpose: Radiation is used extensively to treat localized cancer, but improved understanding of its effects on the immune system has increased interest in its potential systemic (abscopal) effects, particularly in combination with checkpoint inhibitors such as anti-PD1. The majority of patients either do not respond or develop resistance to monotherapy over time. Here, we investigated the efficacy of OX40 (CD134) stimulation as an alternative immunotherapeutic approach in combination with radiotherapy (XRT) in a murine model of anti–PD1-resistant lung tumors.Experimental Design: We established a bilateral tumor model in 129Sv/Ev mice using an anti–PD1-resistant lung tumor cell line. Primary tumors were treated with intratumoral injection of an OX40 agonist antibody, given as adjuvant therapy after XRT (36 Gy in three 12-Gy fractions), whereas secondary tumors were left untreated to investigate abscopal outcomes.Results: The combination of XRT followed by OX40 stimulation effectively inhibited local and systemic antitumor growth, limited lung metastases, and improved survival rates. This treatment regimen augmented CD4+ and CD8+ T-cell expansion. XRT induced the expression of OX40 on T cells in tumors and spleens and increased the percentages of splenic CD103+ dendritic cells.Conclusions: Our data extend the benefits of radiation to systemic disease control, especially when combined with anti-OX40 agonist to promote immunologically mediated abscopal effects. Moreover, this study provides a rational treatment approach and sequence to overcome anti–PD1-resistant poorly immunogenic tumors. Clin Cancer Res; 24(22); 5735–43. ©2018 AACR.

In addition to the conventional knobs such as composition, size, shape, and defect structure, the crystal structure (or phase) of metal nanocrystals offers a new avenue for engineering their properties. Various strategies have recently been developed for the fabrication of colloidal metal nanocrystals in metastable phases different from their bulk counterparts. With a focus on noble metals, we begin with a brief introduction to their atomic packing, followed by a discussion about five major synthetic approaches to their colloidal nanocrystals in unconventional phases. We then highlight the success of synthesis in terms of mechanistic insights and experimental controls, as well as the enhanced catalytic properties. We end this Minireview with perspectives on the remaining issues and future opportunities.

Improving the performance of noble-metal nanocrystals in various applications critically depends on our ability to manipulate their synthesis in a rational, robust, and controllable fashion. Different from a conventional trial-and-error approach, the reduction kinetics of a colloidal synthesis has recently been demonstrated as a reliable knob for controlling the synthesis of noble-metal nanocrystals in a deterministic and predictable manner. Here we present a brief Viewpoint on the recent progress in leveraging reduction kinetics for controlling and predicting the outcome of a synthesis of noble-metal nanocrystals. With a focus on Pd nanocrystals, we first offer a discussion on the correlation between the initial reduction rate and the internal structure of the resultant seeds. The kinetic approaches for controlling both nucleation and growth in a one-pot setting are then introduced with an emphasis on manipulation of the reduction pathways taken by the precursor. We then illustrate how to extend the strategy into a bimetallic system for the preparation of nanocrystals with different shapes and elemental distributions. Finally, the influence of speciation of the precursor on reduction kinetics is highlighted, followed by our perspectives on the challenges and future endeavors in achieving a controllable and predictable synthesis of noble-metal nanocrystals.

Intracytoplasmic sperm injection (ICSI) was first introduced as a supplemental method to conventional in vitro fertilization (c-IVF) for couples with severe male factor infertility to overcome the poor fertilization rate, while its indications expanded in current clinical practice and gained worldwide popularity. However, ICSI is invasive and crosses all natural barriers, raising several unresolved concerns regarding procedure-dependent and procedure-independent risks, as well as the characteristic of being labor-intensive and more expensive than c-IVF. This review is aimed to draw readers' attention, to the widespread use of ICSI worldwide, with its effectiveness in different indications of infertility, especially in those with unexplained infertility, as well as the cost-effectiveness of the ICSI-for-all strategy. Also, we covered current evidence on the short- and long-term safety of children born thanks to ICSI-aided conception. Further well-designed, adequately powered, and randomized controlled clinical trials are absolutely needed to arrive at a consensus on the use of ICSI over c-IVF in different populations.

Background: Embryo quality is an important predictor of successful outcome in in vitro fertilization (IVF). However, current knowledge on the live birth rate after transfer of poor quality embryos is limited. This study investigated the live birth rate after transfer of only poor quality day-3 embryos in women undergoing IVF. Methods: This retrospective study included 153 couples who underwent IVF at IVFMD, My Duc Hospital, Ho Chi Minh City, Vietnam between June 2014 and January 2017 and had only poor quality day-3 embryos available for fresh (n [Formula: see text] 102) or frozen (n [Formula: see text] 51) transfer. The control group included patients who had transfer of one good embryo (n [Formula: see text] 64). Embryos were rated using the Istanbul criteria. Results: In the poor quality embryo group, the mean number of oocytes retrieved and number of embryos were 7.5 ± 4.4 and 1.8 ± 0.9, respectively. Mean number of embryos transferred was 1.6 ± 0.5 in the fresh transfer group and 2.0 ± 0.2 in the freeze-only group. Live births did occur after transfer of poor quality embryos, but the implantation, clinical pregnancy and live birth rates were significantly lower than after fresh or frozen transfer of a single good quality embryo (9.5 vs. 26.6%, p < 0.001; 13.7 vs. 26.6%, p < 0.001; and 7.2 vs. 18.8%, p [Formula: see text] 0.02, respectively). Conclusions: Live birth was achieved after transfer of only poor quality embryos in women undergoing IVF. This suggests that transfer of poor quality embryos could be an option when higher grade embryos are not available, after the chances of live birth have been discussed with the patient.

Background Biotin interference in streptavidin-based immunoassays is known and may lead to erroneous results and thus to diagnostic error. The recent increase in reports of biotin interference in immunoassay-based testing has been attributed to increased intake of biotin supplements by the public and to the high dose biotin therapy in patients with neurological and inherited disorders. Circulating biotin levels greater than 20 ng/mL are reported to exhibit interference in high sensitivity troponin T (hs-TnT), thyroid stimulating hormone (TSH), and in prostate specific antigen (PSA) among other assays when using our Cobas® 6000 immunoassay analyzer (Roche Diagnostics, IN, USA). This study aims to examine the risk for biotin interference among our patient population. Methods Serum and plasma leftover samples from 183 different patients were collected following completion of hs-TnT (53 samples), TSH (45 samples), and PSA (85 samples) testing. Aliquots were stored frozen at -20°C until analysis. Biotin concentrations in these samples were measured using an ELISA (ALPCO, Salem, NH, USA) according to the manufacture's protocol. Samples with biotin levels of 20 ng/mL or greater were considered as high-risk samples (HRS) for biotin interference. Results The overall concentrations of biotin in our patients' samples ranged from 0.02 ng/mL to 11.38 ng/mL (median 0.42 ng/mL). The median and (range) biotin concentrations in hs-TnT, TSH, and PSA samples were 0.27 ng/mL (0.02 - 6.86 ng/mL), 0.39 ng/mL (0.08 - 11.38 ng/mL), and 0.47 ng/mL (0.09 - 7.73 ng/mL), respectively. Although there was no significant difference between biotin levels in samples for TSH or PSA measurement (p = 0.85), biotin in samples for PSA and for hs-TnT and in samples for TSH and hs-TnT were significantly different (p = 0.049 and 0.089), respectively. None of the samples had biotin levels greater than or equal to 20 ng/mL. Conclusions Using representative samples with requests for hs-TnT, TSH, and PSA testing, where reliable performance for the selected assays at their lowest measurement range is required for clinical intervention, among our study population the risk was considered minimal as their circulating biotin levels were less than 20 ng/mL. However, educating clinicians and laboratory users regarding the potential of biotin interference is always recommended.

Rapid advances in Natural Language Processing (NLP) are transforming customer service by making it possible to create chatbot applications that can understand users’ intents and response in a human-like manner. Chatbots promise to enhance customer experiences by creating more personal customer interactions than those afforded by traditional menu-based web applications. But are chatbots always superior to more traditional user interfaces (UI)? This study seeks to understand the differences in user satisfaction with a chatbot system vis-a-vis a menu-based interface system, and identify factors that influence user satisfaction. Grounded in the self-determination theory, the research model proposed here focuses on the effect of chatbot use on perceived autonomy, perceived competence, cognitive load, performance satisfaction, and system satisfaction. An experimental study was conducted, and data were analyzed using Partial Least Square Structural Equation Modeling. The findings indicate that chatbot systems lead to a lower level of perceived autonomy and higher cognitive load, compared with menu-based interface systems, resulting in a lower degree of user satisfaction. Implications of these findings for research and practice are discussed.

Advanced speech recognition technology facilitated the development of voice-based smart devices. Voice user interface (VUI) is now a common feature on smartphones, computers, smart home devices, an...

As organizations manage their reputations on social media, the role of individual stakeholders in responding to online criticism about the organization becomes increasingly important. Building on t...

Circulating prolactin (PRL) exhibits molecular heterogeneity the clinical significance of which is not known. Macroprolactin (mPRL) is widely reported, however, its heterogeneity is unknown. In addition to determining its molecular nature, the relative impact of the various forms on routinely available immunoassays needs to be examined. This study, applied various proteomics techniques to define the nature of mPRL and examined the effect of those forms on its measurement. Methods: Samples suspected of false hyperprolactinemia were subjected to; 1) precipitation by polyethylene glycol, 2) gel permeation chromatography, 3) protein-G affinity chromatography to identify presence of PRL-antibody complex and, 4) samples negative for antibody by step (3) were applied onto a lectin concanavalin A column to examine the presence of glycosylated PRL forms. Analysis was according to manufacturer’s instructions. All study samples and their chromatography fractions were measured using highly sensitive ELISA (DuoSet, R&D Systems, MN). Samples identified above as containing different mPRL forms were analyzed using four immunoassay analyzers in routine clinical use, namely; Advia Centaur® and Atellica® (Siemens, PA), Alinity-ci (Abbott Laboratories, IL), and Cobas 6000® (Roche Diagnostics, IN). Results: A total of 13 samples were entered into the study. PRL levels ranged from 21.4 to 1,469 ng/mL (median 48.8). Samples positive for mPRL (n=8) (with

Bimetallic Janus nanocrystals have received considerable interest in recent years owing to their unique properties and niche applications. The side-by-side distribution of two distinct metals provides a flexible platform for tailoring the optical and catalytic properties of nanocrystals. First, a brief introduction to the structural features of bimetallic Janus nanocrystals, followed by an extensive discussion of the synthetic approaches, is given. The strategies and experimental controls for achieving the Janus structure, as well as the mechanistic understandings, are specifically discussed. Then, a number of intriguing properties and applications enabled by the Janus nanocrystals are highlighted. Finally, this article is concluded with future directions and outlooks with respect to both syntheses and applications of this new class of functional nanomaterials.

Tyro3, Axl, and Mertk (collectively TAM receptors) are three homologous receptor tyrosine kinases that bind vitamin K–dependent endogenous ligands, Protein S (ProS), and growth arrest–specific factor 6 (Gas6), and act as bridging molecules to promote phosphatidylserine (PS)-mediated clearance of apoptotic cells (efferocytosis). TAM receptors are overexpressed in a vast array of tumor types, whereby the level of expression correlates with the tumor grade and the emergence of chemo- and radioresistance to targeted therapeutics, but also have been implicated as inhibitory receptors on infiltrating myeloid-derived cells in the tumor microenvironment that can suppress host antitumor immunity. In the present study, we utilized TAM-IFNγR1 reporter lines and expressed TAM receptors in a variety of epithelial cell model systems to show that each TAM receptor has a unique pattern of activation by Gas6 or ProS, as well as unique dependency for PS on apoptotic cells and PS liposomes for activity. In addition, we leveraged this system to engineer epithelial cells that express wild-type TAM receptors and show that although each receptor can promote PS-mediated efferocytosis, AKT-mediated chemoresistance, as well as upregulate the immune checkpoint molecule PD-L1 on tumor cells, Mertk is most dominant in the aforementioned pathways. Functionally, TAM receptor–mediated efferocytosis could be partially blocked by PS-targeting antibody 11.31 and Annexin V, demonstrating the existence of a PS/PS receptor (i.e., TAM receptor)/PD-L1 axis that operates in epithelial cells to foster immune escape. These data provide a rationale that PS-targeting, anti–TAM receptor, and anti–PD-L1-based therapeutics will have merit as combinatorial checkpoint inhibitors. Implications: Many tumor cells are known to upregulate the immune checkpoint inhibitor PD-L1. This study demonstrates a role for PS and TAM receptors in the regulation of PD-L1 on cancer cells. Mol Cancer Res; 15(6); 753–64. ©2017 AACR.

Circulating prolactin (PRL) exists in several molecular forms with different biological and immunological activities, in some instances making PRL measurements and its diagnostic value unreliable. Macroprolactin (macroPRL), a 150 kDa molecular weight (MW) form, is known to have low biological activity which may lead to misdiagnosis and inappropriate treatment in patients with suspected hyperprolactinemia. Polyethylene glycol precipitation (PEGP) is widely used to identify the presence of macroPRL, but up to 20% of monomeric PRL (23 kDa) is lost during this procedure and PEG itself can interfere with some immunoassays. Additionally, PEGP has been reported to give false positive results for macroPRL in patients with increased serum globulins (IgG myeloma and HIV patients). The aim of this study is to identify different PRL variants in samples suspected of macroPRL using gel filtration chromatography (GFC) Thirteen samples with prolactin levels measured prior to and following PEGP were analyzed using GFC. Briefly, 100 uL of sample or protein markers (MWs ranging from 12.4 to 200 kDa) were applied to a Superdex 200 column (Pharmacia). Forty fractions of 0.5 mL each were collected per patient sample at a flow rate of 0.5 mL/min using PBS containing 0.1% (w/w) bovine serum albumin as the mobile phase. Elution of marker proteins was detected by recording absorbance at 280 nm. To pull down PRL-IgG complexes from our samples, 100 uL of each sample was applied to NAb protein G spin columns (Thermo-Scientific) according to the manufacture’s protocol. The elution and flow-through fractions were collected and analyzed by GFC as described above. PRL concentrations of all GFC fractions were measured using ELISA (RnD systems) according to the manufacture’s protocol. PEGP suggested 8 of our 13 samples were positive for macroPRL, 3 samples had no macroPRL, and 2 samples are within the indeterminate zone (recovery between 40-60%). GFC analyses corelated well with those results, and no macroPRL was present in samples from the indeterminate zone according to GFC. In samples containing macroPRL, 30.8 - 99% of total PRL was bound to protein G columns, while only 0 - 4% of PRL was pulled down from samples negative for macroPRL. Of 8 samples positive for macroPRL, 4 had a fraction of macroPRL that was not bound to protein G columns suggesting the existence of non-IgG-bound macroPRL. GFC analysis showed marked molecular heterogeneity for macroPRL. Mid-molecular weight-PRLs (30-150kDa) were present in every sample, and both high-molecular weight-PRL (>150kDa) and mid-MW-PRL had diverse patterns, but their clinical significance and physiological roles remained unclear. This is the first study to report molecular heterogeneity for macroPRL.

This study examines the relationship between the background of an organization’s top information systems executive or chief information officer (CIO) and what a CIO does. It provides a somewhat different picture of the much discussed relative merits of a CIO’s background. Findings indicate that a technical background has little relationship to what the CIO does once they become CIO. Where they are hired from, however, does relate to reporting line, business focus, and how and with whom they spend their time once hired. These findings will enable more effective CIO hiring and development activities, and inform future research.

Crk, the prototypical member of a class of Src homology-2 (SH2) and Src homology-3 (SH3) domain containing proteins that controls the coordinated assembly of signaling complexes, is regulated by phosphorylation of Y221 in the linker region, which forms an intramolecular SH2-pY221 auto-clamp to interrupt SH2-N-terminal SH3 domain (SH3N) signaling. Here, we show using LC-MS/MS and by generating phospho-specific antibodies that, iteratively with Y221, the Crk C-terminal SH3 domain (SH3C) is routinely phosphorylated on Y239 and/or Y251 by several extracellular stimuli known to engage Crk. Although phosphorylation at Y221 auto-inhibits the Crk SH2, phosphorylation of the SH3C generates an unconventional phosphoSH3C-SH3N unit in which the SH3N is fully functional to bind polyproline type II ligands and the phosphoSH3C binds de novo to other SH2 domains. Using high-throughput SH2 domain profiling, artificial neural network and position-specific scoring matrix-based bioinformatics approaches, and unbiased mass spectometry, we found that the phosphoSH3C binds several SH2 domain containing proteins, including specific non-receptor tyrosine kinases-Abl via pY251 and C-terminal Src kinase via pY239. Functionally, we show that the phosphoSH3C modulates the Abl-mediated phenotypes of cell spreading and motility. Together, these studies describe a versatile mechanism wherein phosphorylation of Crk at Y221 is not an off switch but redirects signaling from the SH2-SH3N axis to a phosphoSH3C-SH3N axis, with the SH3N as a common denominator.

Previous studies have demonstrated that naive splenic mouse T cells express no or only very low levels of the δ-type opioid receptor (δOR), but stimulation of mouse splenocytes with Con A results in induction of δOR mRNA and protein. In this report we have shown that stimulation of highly purified populations of naive mouse T cells with anti-CD3 mAb alone results in T cell activation, as evidenced by sustained IL-2 secretion and cell proliferation, but fails to elicit δOR expression. However, δOR expression is induced by costimulation of these very pure T cells with anti-CD3 and anti-CD28 mAbs. The δOR induction by anti-CD3 and anti-CD28 costimulation was completely blocked by inhibition of phosphatidylinositol 3-kinase with wortmannin. Because phosphatidylinositol 3-kinase activation in T cells is linked to costimulation, these results suggest that induction of δOR expression during T cell activation is strictly dependent on costimulation. It also appears that costimulatory receptors other than CD28 can provide the signaling required for δOR expression because δOR mRNA was induced by Con A stimulation of splenocytes from CD28-deficient mice.

TYRO3, AXL, and MER receptors (TAMs) are three homologous type I receptor-tyrosine kinases that are activated by endogenous ligands, protein S (PROS1) and growth arrest-specific gene 6 (GAS6). These ligands can either activate TAMs as soluble factors, or, in turn, opsonize phosphatidylserine (PS) on apoptotic cells (ACs) and serve as bridging molecules between ACs and TAMs. Abnormal expression and activation of TAMs have been implicated in promoting proliferation and survival of cancer cells, as well as in suppressing anti-tumor immunity. Despite the fact that TAM receptors share significant similarity, little is known about the specificity of interaction between TAM receptors and their ligands, particularly in the context of ACs, and about the functional diversity of TAM receptors. To study ligand-mediated activation of TAMs, we generated a series of reporter cell lines expressing chimeric TAM receptors. Using this system, we found that each TAM receptor has a unique pattern of interaction with and activation by GAS6 and PROS1, which is also differentially affected by the presence of ACs, PS-containing lipid vesicles and enveloped virus. We also demonstrated that γ-carboxylation of ligands is essential for the full activation of TAMs and that soluble immunoglobulin-like TAM domains act as specific ligand antagonists. These studies demonstrate that, despite their similarity, TYRO3, AXL, and MER are likely to perform distinct functions in both immunoregulation and the recognition and removal of ACs.

MERTK, a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases, has complex and diverse roles in cell biology. On the one hand, knock-out of MERTK results in age-dependent autoimmunity characterized by failure of apoptotic cell clearance, while on the other, MERTK overexpression in cancer drives classical oncogene pathways leading to cell transformation. To better understand the interplay between cell transformation and efferocytosis, we stably expressed MERTK in human MCF10A cells, a non-tumorigenic breast epithelial cell line devoid of endogenous MERTK. While stable expression of MERTK in MCF10A resulted in enhanced motility and AKT-mediated chemoprotection, MERTK-10A cells did not form stable colonies in soft agar, or enhance proliferation compared with parental MCF10A cells. Concomitant to chemoresistance, MERTK also stimulated efferocytosis in a gain-of-function capacity. However, unlike AXL, MERTK activation was highly dependent on apoptotic cells, suggesting MERTK may preferentially interface with phosphatidylserine. Consistent with this idea, knockdown of MERTK in breast cancer cells MDA-MB 231 reduced efferocytosis, while transient or stable expression of MERTK stimulated apoptotic cell clearance in all cell lines tested. Moreover, human breast cancer cells with higher endogenous MERTK showed higher levels of efferocytosis that could be blocked by soluble TAM receptors. Finally, through MERTK, apoptotic cells induced PD-L1 expression, an immune checkpoint blockade, suggesting that cancer cells may adopt MERTK-driven efferocytosis as an immune suppression mechanism for their advantage. These data collectively identify MERTK as a significant link between cancer progression and efferocytosis, and a potentially unrealized tumor-promoting event when MERTK is overexpressed in epithelial cells.