cssi/SciSciGPT-SciSciNet huggingface dataset:
24 PROTEIN KINASE C DELTA MEDIATES THROMBIN-INDUCED ENDOTHELIAL BARRIER DYSFUNCTION THROUGH ACTIN STRESS FIBER FORMATION

Pulmonary endothelial cells (EC) maintain vascular barrier integrity through dynamic regulation of the actin cytoskeleton. In response to an inflammatory agonist, such as thrombin, endothelial barrier dysfunction occurs in part through actin stress fiber formation and myosin light chain (MLC) phosphorylation. Protein kinase C (PKCs) belong to a family of serine/threonine kinases, which have been implicated in barrier regulation, but the role of specific PKC isoforms in mediating thrombin-induced barrier dysfunction in human pulmonary endothelium is unclear. PKCδ is highly expressed in human lung EC and is activated in response to thrombin. Using pharmacological (rottlerin) and molecular (AdDN PKCδ) approaches to inhibit PKCδ, we assessed the role of PKCδ in regulating stress fiber formation, MLC phosphorylation, and barrier function. Inhibition of PKCδ attenuated both thrombin-induced actin stress fiber formation and endothelial barrier dysfunction, but not MLC phosphorylation. Since actin stress fiber formation and MLC phosphorylation are downstream effectors of RhoA via mDia and Rho kinase signaling pathways, respectively, we examined the relationship between RhoA and PKCδ. Overexpression of constitutive active RhoA resulted in PKCδ activation and stress fiber formation, both of which can be blocked with rottlerin treatment. In addition, Y-27632 (10 μM), a Rho kinase inhibitor, blocked thrombin-induced MLC phosphorylation and attenuated endothelial barrier dysfunction suggesting PKCδ does not signal through RhoA-Rho kinase pathway. Since PKCδ inhibition improved barrier restoration upon thrombin challenge, we next examined the effect of PKCδ inhibition on the barrier-enhancing agent, sphingosine 1-phosphate (S1P), which induces a rapid and sustained endothelial barrier enhancement. PKCδ inhibition delineates cortical actin formation and augments the S1P response. Taken together, our data demonstrate that PKCδ is a downstream target of RhoA and plays a barrier disruptive role in mediating thrombin-induced stress fiber formation and negatively regulating the barrier-enhancing response of S1P.
Abstract IA27: Retooling CRISPR to turn genes on and off

CRISPR (clustered regularly interspaced short palindromic repeats) is an adaptive genome defense system in bacteria and archaea. CRISPR has been widely repurposed as an RNA-guided genome editing method. We have shown that the endonuclease domains of the Cas9 protein can be mutated to create a programmable RNA-guided DNA-binding protein. In human cells, we have shown we can control transcription of endogenous coding and non-coding genes over a wide range (up to 1000 fold) by using dCas9 chimeras to deliver protein domains that either repress (CRISPRi) or activate (CRISPRa) transcription. These experiments provide proof of principle that we can use dCas9 as an RNA-guided DNA binding platform to deliver in theory any protein to a specific genomic location, which may be useful for studying transcription, epigenetic regulation, DNA replication and DNA repair. We have developed a genome-scale CRISPRi/a functional genomics platform for loss- and gain-of-function screening in human cells. We have demonstrated that our CRISPRi/a screening platform can robustly identify pathways and proteins required for cancer cell growth and survival. Gain-of-function CRISPRa screens promise to reveal a layer of genetic information missing from previous efforts. We have shown in a cell growth screen that CRISPRa reveals latent tumor suppressors and transcription factors that regulate cancer cell state in chronic myeloid leukemia cells. In proof of principle, we have also used CRISPRi/a screens to determine the mechanism of cellular uptake, trafficking, retro-translocation, and toxicity for a chimeric bacterial toxin. These experiments establish CRISPRi and CRISPRa as powerful tools that provide rich and complementary information for mapping complex pathways. Recently, we have used our CRISPRi/a functional genomics platform to determine the genetics of cellular response to HSP70 inhibitors, which are a new class of anti-cancer drugs targeting a non-oncogene addiction. Together, our experiments demonstrate the utility of our CRISPRi/a functional genomics approach for studying principles of oncogene and non-oncogene addiction in cancer biology and cancer therapy. Citation Format: Luke A. Gilbert, Max A. Horlbeck, Jacqueline Villalta, Shao Hao, Jason E. Gestwicki, Jonathan S. Weissman. Retooling CRISPR to turn genes on and off. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr IA27.
Structural and Conformational Analogues of L-Methionine as Inhibitors of the Enzymatic Synthesis of S-Adenosyl-L-Methionine : II. Aromatic Amino Acids

A series of aromatic amino acids structurally related to L-methionine were synthesized as potential inhibitors of the enzymatic formation of S-adenosyl-L-methionine by partially purified preparations of ATP:L-methionine S-adenosyltransferase (EC 2.5.1.6) of bakers’ yeast, Escherichia coli, and rat liver. 2-Amino-5-phenylpentanoic acid was a considerably better inhibitor of the liver enzyme than 2-aminopentanoic acid (norvaline) but produced no inhibition of the yeast and E. coli enzymes. (E)-2-Amino-5-phenyl-4-pentenoic and 2-amino-5-phenyl-4-pentynoic acids were superior in their inhibitory activity to the corresponding chain-saturated analogues. The phenyl group thus imparts a favorable influence on the inhibitory power. S-Phenyl-DL-homocysteine is an even more potent inhibitor of the liver enzyme, but is also devoid of activity in the microbial enzyme systenms. O-Phenyl-DL-homoserine displays similar properties, but was not quite as effective as the sulfur analogue. In order to evaluate the effect of electron-donating and electron-withdrawing substituents on the phenyl ring, the following compounds were synthesized: O-(p-fluorophenyl)-DL-homoserine, O-(p-chlorophenyl)-DL-homoserine, O-(p-bromophenyl)-DL-homoserine, O-(p-nitrophenyl)-DL-homosenine, O-(p-methoxyphenyl)-DL-homoserine, O-(p-methylphenyl)-DL-homoserine, O-(m-chorophenyl)-DL-homoserine, O-(m-bromophenyl)-DL-homoserine, O-(m-nitrophenyl)-DL-homoserine, and O-(m-methoxyphenyl)-DL-homoserine. When the inhibitory potencies of these compounds (expressed as pI50 values) were analyzed in terms of the Hammett σ values of the substituents, the inhibitory potency was correlated with the positive magnitudes of the σ values. If the anomalous nitro compounds are excluded, the Hammett sigma-rho equation PI50 = 1.45σ + 1.82 is obtained by least-squares linear regression analysis. This finding suggests that the electron-withdrawing substituents are most favorable for inhibition, and that the creation in the analogue of a partial positive charge at the heteroatom bearing the phenyl group may resemble most closely the transition state of the enzymatic reaction, in which the thioether group of L-methionine is converted to the positively charged sulfonium group of S-adenosyl-L-methionine. O-Methyl-DL-homoserine is a strong inhibitor of the adenosyltransferases of yeast, E. coli, and rat liver, and especially powerful for the E. coli enzyme. Since it has been shown that this compound inhibits the growth of certain microorganisms and viruses, as well as displaying certain specific toxicities in rodents the possibility should be considered that these effects are due to inhibition of the adenosyltransferase reaction.
Opportunistic Infections in Elasmobranchs

This chapter describes factors potentially contributing to immunosuppression and thus opportunistic infections in captive and free-ranging cartilaginous fishes. The immune system in sharks is briefly discussed to show the similarities with higher vertebrates with the implications for comparable mechanisms governing immunosuppression. A brief description of stress as a factor inducing immunosuppression is provided. Potentially opportunistic infections with viruses, bacteria, algae, and parasites are discussed separately for elasmobranchs in captivity and in the wild, and their links with stress-inducing stimuli are suggested.
Casey Hayden and Mary King

In 1964–65, some young white women in sncc began to examine their roles. Why did they do all the “shit work” and not share in the decision making or public speaking? Based on months of informal conversations, the respected movement veterans Mary King and Casey Hayden circulated this memo to young women around the country. Their goal was simply to start a dialogue about women’s exclusion from structures of power and their subordination in personal relationships. Although King and Hay-den thought that “the chances seem nil that we could start a movement based on anything as distant to general American thought as a sex-caste system,” that is exactly what happened. The memo noted that male radicals’ usual response to discussions of women’s oppression was laughter. This pattern of derision, repeated over several years, eventually led many of these women to leave male-dominated organizations.
Models of Cholinergic Degeneration: AF64A and 192-IgG-Saporin

Selective toxins have been widely used in neurobiology to unravel the molecular, cellular, anatomical, and physiological correlates of brain organization and function. They have also been used to examine the cellular events that contribute to neurodegeneration and to model neurodegenerative diseases. Cholinergic neurons in the basal forebrain are affected early in the course of Alzheimer’s disease (AD) and their compromise is related to the severity of cognitive symptoms (reviewed in Walsh and Chrobak, 1991). Therefore, neurotoxins selective for cholinergic neurons should be useful tools to explore the functional biology of cholinergic systems and to model diseases of cholinergic hypofunction such as AD. The focus of this chapter is on how two specific neurotoxins, AF64A (ethylcholine mustard aziridinium) and 192-IgG-saporin, have been used to study aspects of AD. The behavioral effects of these compounds have been reviewed elsewhere (Walsh et al., 1994; 1996). Both of these compounds offer unique advantages and disadvantages to the investigator. Their careful use should provide complimentary information about: (i) the cellular and molecular mechanisms responsible for degeneration of cholinergic neurons; (ii) the functional consequences of that degeneration, and (iii) potential targets for thera peutic intervention that might retard or prevent neurodegeneration and/or promote survival of cholinergic neurons in early stages of degeneration.
Bilateral Carotid-Cavernous Fistulas: An Uncommon Cause of Pituitary Enlargement and Hypopituitarism

Carotid-cavernous fistulas (CCFs) are rare, pathologic communications of the carotid artery and the venous plexus of the cavernous sinus. They can develop spontaneously in certain at risk individuals or following traumatic head injury. Typical clinical manifestations include headache, proptosis, orbital pain, and diplopia. We report a case of bilateral carotid-cavernous fistulas associated with these symptoms and also with pituitary enlargement and hypopituitarism, which improved following surgical intervention. Arterialization of the cavernous sinus and elevated portal pressure may interfere with normal venous drainage and the conveyance of inhibiting and releasing hormones from the hypothalamus, resulting in pituitary enlargement and hypopituitarism. This condition should be considered in the differential diagnosis of hypopituitarism associated with anterior pituitary enlargement.
Cranberry extract initiates intrinsic apoptosis in HL-60 cells by increasing Bad activity through the inhibition of Akt phosphorylation

Cranberry’s role as a potential chemopreventive agent has been examined by various studies since 1996. One of the proposed mechanisms is to eliminate cancerous cells by inducing apoptosis. A limite...
Iron Deficiency Anemia

Iron deficiency is one of the most common causes of anemia. The 2 main etiologies of iron deficiency are blood loss due to menstrual periods and blood loss due to gastrointestinal bleeding. Beyond anemia, lack of iron has protean manifestations, including fatigue, hair loss, and restless legs. The most efficient test for the diagnosis of iron deficiency is the serum ferritin. Iron replacement can be done orally, or in patients in whom oral iron is not effective or contraindicated, with intravenous iron.
Synthesis of Cellulose-g-Polystyrene by Anionic Polymerization

The forced union by block and graft polymerization of synthetic polymers to natural polymers such as cellulose can lead to materials with unusual and useful properties for differing applications. Graft copolymerization is an attractive means for modifying base polymers because grafting frequently results in the superposition of properties relating to backbone and side chains [1], Grafting is especially useful when the backbone and side chain homopolymers are incompatible. Special properties of graft copolymers that lead to potential or actual applications are changes in permeability, solubility, compatibility, and the mosaic structure of the solid state [2]
Pharmacologic Treatment Options for Bipolar Disorder in Children and Adolescents

Purpose of review Bipolar disorder is a chronic and disabling condition that often presents in adolescence and leads to significant functional impairment, especially in the areas of emotional, cognitive, and social development. Pharmacotherapy is a vital component of the complex treatment of this disorder.The purpose of this review is to provide an overview of the available data on the management of bipolar disorder and the most common comorbid conditions in youth. Recent findings Several medications such as lithium and second-generation antipsychotics (risperidone, aripiprazole, olanzapine, quetiapine, and asenapine) are currently approved by the FDA for the management of acute mixed or manic phases of pediatric bipolar disorder. Very limited data are available on continuation treatment and management of depressive phases of bipolar disorder. There is some evidence that supports the use of a combination of an antipsychotic with lithium or an anticonvulsant for treatment of resistant cases. Summary Monotherapy with an atypical antipsychotic or lithium is the preferable initial treatment of acute manic or mixed episodes. The available evidence supports the use of an olanzapine/fluoxetine combination for the treatment of bipolar depression, which has also been approved by the FDA for this purpose. Additional studies are needed to evaluate safety and efficacy of psychopharmacological interventions, especially focusing on treatment of the depressive and maintenance phases of bipolar disorder.
A randomized study comparing the pharmacokinetics of the potential biosimilar PF-06438179/GP1111 with Remicade® (infliximab) in healthy subjects (REFLECTIONS B537-01).

ABSTRACTBackground: To demonstrate pharmacokinetic (PK) similarity of PF-06438179/GP1111, a potential biosimilar to Remicade®, to Remicade® sourced from European Union (infliximab-EU) and United St...
Chalazion in multiple myeloma patients treated with bortezomib.

e13053 Background: Bortezomib, a proteosome inhibitor is an effective drug in treatment of multiple myeloma (MM). As single agent and in combination with other drugs it not only has antitumor effec...
Ready ⃛ aim ⃛ fire

The so-called SNARE hypothesis suggests that membranes bearing v- (for donor vesicle) and t- (for target membrane) SNAREs join and fuse to assemble membranes. This view is now challenged by two studies that define three distinct stages in the fusion pathway, and show that formation of a v-t-SNARE complex is, in fact, separable from membrane fusion.
A Comparison of Conjoint Analysis with Other Approaches to Model Physician Policies in Scoring Complex Performance-Based Assessment

Scoring performance assessment requires expert judgments that combine and weight various features of performance to produce a measure. Building models of these policies and mechanically applying them is potentially advantageous where the number of judgments would exhaust the number of available raters. Conjoint analysis is presented as a technique to score computer-based case simulations (CCS) developed by the National Board of Medical Examiners and intended for use in licensure assessment in the United States. To study this technique, four CCSs were selected from those administered to medical students. A four-member clinician committee defined performance attributes (diagnosis, therapy, monitoring, timing) and levels of each; from this, performance profiles were generated for review. Then, each expert individually assigned an anchored rating from 1 (worst) to 9 (best) to each profile; individual rating disagreements on the same examinee performance of more than one were discussed. From this, expert policies were applied to produce examinee case scores.
The origin of lunar concentric craters

Abstract Lunar concentric craters are a unique class of impact craters because the interior of the craters contains a concentric ridge, but their formation mechanism is unknown. In order to determine the origin of concentric craters, we examined multiple working hypotheses, which include eight impact-related and endogenic processes. We analyzed data sets that originated from instruments onboard Clementine, Kaguya, and the Lunar Reconnaissance Orbiter to characterize the morphology, spatial distribution, composition, and absolute model ages of 114 concentric craters. Concentric craters contain five key properties: (1) a concentric ridge, (2) anomalously shallow floors, (3) their occurrence is concentrated near mare margins and in mare pond regions (4) the concentric ridge composition is similar to the surrounding area and (5) concentric crater ages are Eratosthenian and older. These five key properties served as constraints for testing impact-related and endogenic mechanisms of formation. We find that most impact-related hypotheses cannot explain the spatial and age distribution of concentric craters. As for endogenic hypotheses, we deduce that igneous intrusions are the likely mechanism that formed concentric craters because of the close relationship between concentric craters and floor-fractured craters and the concentration of both features near mare-highland boundaries and in mare ponds. Furthermore, we observe that floor-fractured craters are common at crater diameters > 15 km, whereas concentric craters are common at crater diameters 15 km) produce floor-fractured craters.
Addition of Anti-CD40 Monoclonal Antibody to Nonmyeloablative Conditioning With Belatacept Abrogated Allograft Tolerance Despite Induction of Mixed Chimerism

BackgroundWe recently reported anti-CD40 monoclonal antibody and rapamycin (aCD40/rapa) to be a reliable, nontoxic, immunosuppressive regimen for combined islet and kidney transplantation (CIKTx) in nonhuman primates. In the current study, we attempted to induce allograft tolerance through the mixed
The Paradox of Preference vs. Performance: Towards a Unified View of Simulation Experience:

Interactive simulation is one of the most prominent methods used to train and measure learning outcomes across multiple disciplines. Despite the ubiquity of simulation-based training in a variety o...
Pharmacologic ascorbate induces DNA damage, alters the bioenergetic profile, but does not influence cellular respiration or glycolysis in human pancreatic cancer cells

We have investigated the effects of high dose ascorbate, (pharmacological ascorbate, P-AscH-) as an adjuvant to common cancer treatment modalities. We have proposed that P-AscH- acts as a pro-drug for delivery of extracellular H2O2 to tumors. This H2O2 enhances or exacerbates DNA damage. Many cancer treatment modalities, whether biophysical (ionizing radiation) or chemical (drug), are believed to involve direct damage to DNA or inhibit DNA repair processes. We have observed that DNA damage occurs in both nuclear as well as mitochondrial DNA in human pancreatic cancer cell lines upon exposure to P-AscH- with concomitant decreases in NAD+, NADH, and ATP. After removal of ascorbate, all the above resolve with time suggesting a link to cellular bioenergetics. To address steady-state changes in these redox-related species, we used Seahorse XF analysis. In media as ascorbate oxidizes it consumes oxygen in a concentration-dependent manner; this could lead to misinterpretation of data on cellular bioenergetics. To avoid this we incubated cells (0.5 to 1 h) with lethal doses of P-AscH- and then rapidly removed it before initiating bioenergetic experiments. We detected no significant changes in cellular bioenergetics following lethal doses (clonogenic) of P-AscH- at 0.5 h and up to 24 h after exposure. These results indicate that the decreased levels of NAD+, NADH, and ATP observed following short-term exposure to P-AscH- is not due to decreased production but rather due solely to increased demand. In additional experiments we observed no changes in metabolism upon exposure to dehydroascorbate (DHA) or ascorbate 2-phosphate, forms that load cells with ascorbate, but produce no extracellular H2O2. These data indicate that P-AscH- generates extracellular H2O2 leading to DNA damage resulting in depletion (demand) of cellular NAD+, NADH, and ATP. There appears to be no bioenergetic crisis due to a loss (production) in bioenergetic capacity.
Effect of Mach number and volume fraction in air-shock interacting with a bed of randomly distributed spherical particles

Shock interaction with a bed of randomly distributed particles leads to large variation in the drag forces, highlighting the impact of neighboring particles, and indicating a need for point-particle force models that account for this drag variation.
Abstract 829: SOX2-mediated 5hmC dysregulation in GBM stem cells

Primary brain tumors are among the most devastating forms of cancer and glioblastoma (GBM) represents the most aggressive and lethal form of the disease. We now know that GBM contain small subsets of cells that display tumor-propagating stem-like phenotypes (i.e. glioma stem cells or GSCs) that act as critical determinants of GBM resistance to current treatments and tumor recurrence for which there is no proven therapy. Altered patterns of DNA methylation are widely reported in human GBM. However, substantial knowledge gaps remain in our understanding of the molecular mechanisms responsible for this epigenetic dysregulation, its downstream consequences and role in the GBM tumor propagating phenotype. Understanding and ultimately targeting the epigenetic mechanisms that induce and maintain these tumor-propagating cell subsets is critical to improving GBM therapy and patient outcomes. DNA methylation generally occurs in cytosine-guanine (CpG) sequences and is established by DNMTs, which catalyze the conversion of cytosine to 5-methylcytosine (5mC). DNA methylation is a reversible process and is partially mediated by the ten-eleven translocation (TET) family of enzymes which function as deoxygenases to catalyze the conversion of 5mC to 5-hydroxymethylcytosine (5hmC). Levels of 5hmC closely track with the differentiation state of cells with terminally differentiated cells containing high levels of 5hmC and less differentiated cells having very low levels. Multiple studies found negative correlations between 5hmC levels and glioma grade and loss of 5hmC correlates with poor prognosis of GBM patients, strongly suggesting that these enzymes activate tumor suppressing mechanisms. Our preliminary data shows that exogenous SOX2 represses the TET2 demethylase and decreases 5hmC, the enzymatic product catalyzed by TET proteins, in GSCs. TET2 repression using 2 independent shRNA hairpins efficiently decreases 5hmc levels and significantly enhanced self-renewal capacity and tumor growth capacity of low-passage GSC isolates. We also show that SOX2 induces expression of miR-10b-5p, a known onco-miR predicted to target TET2, and inhibiting this miRNA partially rescues the reduction in 5hmC expression observed in GSCs expressing transgenic SOX2, thus implicating miR-10b-5p as a critical mediator of SOX2-induced onco-methylation, GSC induction and glioma malignancy. Our preliminary results support a mechanism in which SOX2 represses TET2 leading to 5hmC loss by directly activating miR-10b-5p transcription and predicts that targeting this novel mechanism of epigenetic dysregulation by inhibiting miR-10b-5p in vivo will can lead to pre-clinical GBM therapeutics. Citation Format: Hernando Lopez-Bertoni. SOX2-mediated 5hmC dysregulation in GBM Stem Cells [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-059.
Collective multipole oscillations direct the plasmonic coupling at the nanojunction interfaces

We present a systematic study of the effect of higher-multipolar order plasmon modes on the spectral response and plasmonic coupling of silver nanoparticle dimers at nanojunction separation and introduce a coupling mechanism. The most prominent plasmonic band within the extinction spectra of coupled resonators is the dipolar coupling band. A detailed calculation of the plasmonic coupling between equivalent particles suggests that the coupling is not limited to the overlap between the main bands of individual particles but can also be affected by the contribution of the higher-order modes in the multipolar region. This requires an appropriate description of the mechanism that goes beyond the general coupling phenomenon introduced as the plasmonic ruler equation in 2007. In the present work, we found that the plasmonic coupling of nearby Ag nanocubes does not only depend on the plasmonic properties of the main band. The results suggest the decay length of the higher-order plasmon mode is more sensitive to changes in the magnitude of the interparticle axis and is a function of the gap size. For cubic particles, the contribution of the higher-order modes becomes significant due to the high density of oscillating dipoles localized on the corners. This gives rise to changes in the decay length of the plasmonic ruler equation. For spherical particles, as the size of the particle increases (i.e., ≥80 nm), the number of dipoles increases, which results in higher dipole–multipole interactions. This exhibits a strong impact on the plasmonic coupling, even at long separation distances (20 nm).
Hematopoietic Phf6 Deletion in Mice Causes HSC Depletion and Expansion of Myeloid Progenitors

PHF6 is an X-chromosome gene showing recurrent loss-of-function mutations in acute and chronic myeloid leukemias and T-lymphoblastic leukemia, indicating that it acts as a tumor suppressor in both myeloid and lymphoid hematopoietic lineages. PHF6 protein is localized to the nucleolus, the site of ribosome biogenesis, where it is reported to regulate rDNA transcription. It is also localized to the nucleoplasm, where it binds chromatin and may regulate gene transcription. However, these mechanisms are incompletely established, no animal model of PHF6 loss has been reported, and there is limited insight into the precise role of PHF6 in hematopoiesis, both mechanistically and as a leukemia suppressor. To study the in vivo role of Phf6, we generated mice with hematopoietic knockout of Phf6 using the Vav-Cre recombinase system, achieving a >95% deletion efficiency. In comparison with Vav-Cre mice (WT), mice with Vav-Cre;Phf6-flox genotype (Phf6 KO) showed, at 8-12 weeks of age, a 1.25-fold expansion of the LSK (Lin-Sca1+Kit+) compartment in the bone marrow (see figure), accompanied with a similar increase in the common myeloid progenitor CMP compartment (Lin-Kit+Sca1-CD34+FcRIII-). Within the LSK compartment, there was a 2-fold and 1.7-fold expansion of the myeloid-biased multipotent progenitor compartments MPP2 (LSK,Flk2-CD150+CD48+) and MPP3 (LSK,Flk2-CD150-CD48+) respectively. The lymphoid-biased MPP4 compartment was not changed, nor was the common lymphoid progenitor CLP compartment (not shown). Conversely, the number of stringently defined HSCs (LSK,Flk2-CD150+CD48-CD34-) was reduced by 40%. This suggests depletion of HSCs through loss of dormancy, accompanied by myeloid skewing. At 8-12 weeks of age, there was no change in overall bone marrow cellularity or spleen size/cellularity, though flowcytometric analysis of spleen showed identical reduction of HSC and expansion of MPP2 compartments in Phf6 KO. As of 40 weeks of age, Phf6 KO mice did not show any gross peripheral blood count abnormalities. We also used CRISPR/Cas9 to generate PHF6 knockout clones from the THP-1 human AML cell line. RNA-Seq and quantitative proteomics in knockout cells showed downregulation of mature myeloid genes and increased expression of hematopoietic progenitor gene sets, including increased expression of cell surface receptor KIT. KO cells showed increased proliferation when cultured with KIT ligand. Using IP-mass spectrometry in WT and KO clones, we identified ribosomal proteins RPL12 and RPLP0 as the most abundant and specific binding partners of PHF6. In summary, young Phf6 knockout mice show HSC depletion and expansion of myeloid-skewed progenitors without overt peripheral blood abnormalities. Further work is in progress to characterize HSC dormancy and competitiveness, progression of Phf6 KO phenotype with age, and mechanisms of gene regulation by Phf6 through binding of ribosomal proteins. Disclosures No relevant conflicts of interest to declare.
New Methods for the Cross-Section of Returns

The cross-section and time series of stock returns contains a wealth of information about the stochastic discount factor (SDF), the object that links cash flows to prices. A large empirical literature has uncovered many candidate factors—many more than seem plausible—to summarize the SDF. This special volume of the Review of Financial Studies presents recent advances in extracting information from both the cross-section and the time series, in dealing with issues of replication and false discoveries, and in applying innovative machine-learning techniques to identify the most relevant asset pricing factors. Our editorial summarizes what we learn and offers a few suggestions to guide future work in this exciting new era of big data and empirical asset pricing.
A model for reputation rank in online social networks and its applications

The volume of information users upload through online social networks (OSNs) is continuously growing. Our focus in this research is in evaluating models to quantify the volume and strengths of interactions between users in OSNs. In our first model, we proposed a reputation rank in OSNs based on a tree graph in which users represent the tree nodes and edges represent their friends' connections or their generated activities. In each OSN such as Facebook, Twitter, LinkedIn, etc. each user will be given a single value that represents the user created activities and friends' interactions with those activities. The model focuses on volumes and statistics of interactions, rather than the content. We also extended the use of cliques' models in OSNs to be normalised or weighted based on the volumes of interactions among clique members. We showed that this can show deeper knowledge of clique relations when comparing it with the classical non-weighted clique models.
Influence of Nanoarchitecture on Charge Donation andthe Electrical-Transport Properties in [(SnSe) 1+δ ][TiSe 2 ] q Heterostructures

A series of [(SnSe)1+δ][TiSe2]q heterostructures with systematic changes in the number of TiSe2 layers in the repeating unit were synthesized, and both the structure and electronic-transport proper...
Staying Quiet or Speaking Out: Does Peer Reporting Depend on the Type of Counterproductive Work Behavior Witnessed?

Abstract. Peer reporting, which occurs when employees report the occurrence of coworkers’ counterproductive work behavior (CWB) to organizational authorities, may help management detect CWBs that w...
This land is our land: the struggle for a new commonwealth

The climate emergency seems so intractable in part because of the obduracy of the agricultural and industrial infrastructure we have embedded in our landscape over the past two centuries. However, ...
Breast tumor kinase (Brk/PTK6) mediates advanced cancer phenotypes via SH2-domain dependent activation of RhoA and aryl hydrocarbon receptor (AhR) signaling

Protein tyrosine kinase 6 (PTK6; also called Brk) is overexpressed in 86% of patients with breast cancer; high PTK6 expression predicts poor outcome. We reported PTK6 induction by HIF/GR complexes in response to either cellular or host stress. However, PTK6-driven signaling events in the context of triple-negative breast cancer (TNBC) remain undefined. In a mouse model of TNBC, manipulation of PTK6 levels (i.e., via knock-out or add-back) had little effect on primary tumor volume, but altered lung metastasis. To delineate the mechanisms of PTK6 downstream signaling, we created kinase-dead (KM) and kinase-intact domain structure mutants of PTK6 via in-frame deletions of the N-terminal SH3 or SH2 domains. While the PTK6 kinase domain contributed to soft-agar colony formation, PTK6 kinase activity was entirely dispensable for cell migration. Specifically, TNBC models expressing a PTK6 variant lacking the SH2 domain (SH2-del PTK6) were unresponsive to growth factor-stimulated cell motility relative to SH3-del, KM, or wild-type PTK6 controls. Reverse-phase protein array revealed that while intact PTK6 mediates spheroid formation via p38 MAPK signaling, the SH2 domain of PTK6 limits this biology, and instead mediates TNBC cell motility via activation of the RhoA and/or AhR signaling pathways. Inhibition of RhoA and/or AhR blocked TNBC cell migration as well as the branching/invasive morphology of PTK6+/AhR+ primary breast tumor tissue organoids. Inhibition of RhoA also enhanced paclitaxel cytotoxicity in TNBC cells, including in a taxane-refractory TNBC model. IMPLICATIONS: The SH2-domain of PTK6 is a potent effector of advanced cancer phenotypes in TNBC via RhoA and AhR, identified herein as novel therapeutic targets in PTK6+ breast tumors.
Obesity in Children/Adolescents and Obesity-Related Comorbidities

Childhood obesity is a growing concern, which may result in major comorbidities, previously felt to be adult-specific diseases. Genetics, environment, and behavior count among the pillars of this condition. Lifestyle modification is paramount, whereas indications for metabolic and bariatric surgery are becoming popular as well for severely affected adolescents. The scarcity of approved drugs progressively leads to off-label adjunct prescriptions in those refractories to diet and exercise. Comorbidities can persist into later life- impacting morbidity and mortality. Besides prevention and treatment of ongoing problems, long-term sequelae should be avoided to allow for a long and healthy adult life.
Deep learning-based denoising in spectrally-encoded confocal microscopy

In this paper, we demonstrate deep learning-based denoising of high-speed (180 fps) confocal images obtained with our low-cost SECM device. The CARE network was trained with 3090 high- and low-SNR image pairs on the Google Colab platform and tested with 45 unseen image pairs. The CARE prediction showed significant increase of SSIM and PSNR, and reduction of the banding noise while maintaining the cellular details. The preliminary results show the potential of using a deep learning-based denoising approach to enable high-speed SECM imaging.
Land, Edwin Herbert 1909–1991

Edwin Land was born on May 7, 1909, in Bridgeport, CT, to Harry and Martha Land. He was educated at Norwich Free Academy in Norwich, CT, where he graduated with honors. He spent one year at Harvard University studying chemistry, dropped out and moved to New York City. He educated himself at the New York Public Library and experimented after hours at a Columbia University laboratory where he invented the Polaroid J sheet, an arrangement of microscopic crystals on a plastic sheet filtering out certain kinds of polarized light, used for example in sunglasses. He obtained a patent for it in 1929. He returned to Harvard where he concentrated on chemistry and physics. He and a partner formed a company that produced polarized sheets, named Polaroid Corporation in 1937. During World War II, the company developed new kinds of night vision goggles and a system that could reveal enemies in camouflage uniforms. When in New Mexico in 1944, Land’s three-year-old daughter Jennifer asked him why the camera he used could not immediately produce an image. This got Land to think about such possibilities, and early in 1947, the Polaroid Model 95 camera and the related Type 40 Land film producing black-and-white images began to be offered on the market. The system soon became a big success.
Time and Philosophy: A History of Continental Thought

Since Kant, the past two centuries of continental philosophy have produced an extraordinary range of ways of thinking about the world and the self. But this diversity of thought has worked to obscure a sense of common interests, of a coherent history. Time and Philosophy presents a detailed survey of continental thought through a historical account of its key texts. The common theme taken up in each text is how philosophical thought should respond to time. The book examines the development of continental philosophy in both Europe and America, with discussions ranging from Hegel, Marx, Kierkegaard, Nietzsche, Husserl, Heidegger, Arendt, Adorno and Horkheimer, Sartre, Beauvoir, Foucault and Derrida to the most influential thinkers of today, Agamben, Badiou, Butler and Ranciere. Throughout, the concern is to elucidate the primary texts for readers coming to them for the first time. But, beyond this, Time and Philosophy aims to reveal the philosophical rigour that underpins and connects the history of continental thought.
The Means of Distinguishing between Hydrogen Secretion and Bicarbonate Reabsorption: Theory and Applications to the Reptilian Bladder and Mammalian Kidney

Publisher Summary When the concentration of luminal HCO 3 remains fixed or increases during reabsorption, factors such as bulk flow and sieving complicate the interpretation of methods currently used to identify the acidification mechanism. This chapter discusses the theoretical and experimental methods used to distinguish one type of acidification mechanism from another—first, in a general sense, second, in the particular case of the reptilian bladder, and third, in the particular case of the mammalian renal tubule. The weight of available evidence supports the concept that an active HCO 3 transport is the mechanism of luminal acidification in the turtle bladder. This mechanism is the unique explanation for the data on decreasing luminal [CO 2 ] during acidification and is a fully adequate explanation for increasing luminal [CO 2 ] during acidification, H-accumulation in a luminal fluid initially devoid of HCO 3 and CO 2, and the HCO 3 -sensitive short-circuiting current.
Toleration, Social Identity, and International Justice in Rawls and Hegel

Like Hegel, Rawls acknowledges the immense importance of recognizing and respecting the value of cultural affiliation and its role in facilitating social identity. However, Rawls misunderstands the nature of social identity and the conditions required for its realization. His adoption of toleration as a norm fundamental to international principles of justice does not satisfactorily explain why culture ought to be respected and, more importantly, why respect for culture justifies some human rights violations. Hegel agrees with Rawls’ conclusion that the international realm cannot be governed by the same principles of justice that govern relations between individuals at the domestic level, but according to Hegel, this does not mean that we ought to abandon the liberal principle of individual rights. Hegel’s political philosophy shows not only why social identity is important, but how it can be reconciled with a strong doctrine of individual rights.
TH-AB-204-09: High-Sensitivity L-Shell X-Ray Fluorescence CT Imaging of Gold

Purpose: To experimentally demonstrate the feasibility of L-shell x-ray fluorescence CT (XFCT) imaging of gold contrast. Methods: We have built an experimental L-shell XFCT imaging system consisting of two photon-counting detectors, a silicon drift detector (SDD) and a CdTe detector, a miniature x-ray tube, and a programmable translation/rotation stage. A 2.8-mm diameter water phantom containing 4-mm vials with gold solutions of 0.06%, 0.08%, and 0.1% Au located at 4mm depth was constructed. The phantom was imaged with the L-shell XFCT system in 1st generation CT geometry with a 1-mm 50-kV x-ray beam. XFCT data was acquired with both detectors placed at ±120° with respect to the excitation beam at 30 translation and 36 rotation steps. L-shell XFCT images were reconstructed with maximum-likelihood expectation-maximization using gold Lα and Lβ fluorescence x-rays for both detectors. Results: SDD L- shell x-ray fluorescence (XRF) signal was approximately 13 times higher than CdTe XRF signal due to the higher measured SDD energy resolution of 220eV @ 14keV compared to the CdTe energy resolution of 660eV. While all 0.06–0.1% Au vials were detectable in the SDD L-shell XFCT image, none of the vials were visible in the CdTe L-shell XFCT image. The contrast-to-noise ratio of the 0.1% Au vial was 87.1 and 3.2 in the SDD and CdTe L-shell XFCT images, respectively. SDD L-shell XFCT signal was linear with Au concentration (R2>0.99). The detectability limits of the presented L-shell XFCT imaging setup were 0.007% and 0.126% Au for L-shell XFCT imaging performed with the SDD and CdTe detector, respectively. Conclusion: We have demonstrated the feasibility of L- shell XFCT imaging of gold located at shallow depths inside a small animal sized phantom. The very high sensitivity of L-shell XFCT, permitting detection of Au concentrations as low as 0.06%, has not previously been achieved experimentally using conventional K-shell XFCT.
Why It Is Better To Be Married

There were a pair of dusty old oxen, who had been pulling things for years under the same yoke. Suddenly, after years of silence, one of the oxen turned in his bow to the other and mooed, isn't it time we fell in love and got married? Why should that happen? lowed the other ox. Because we've been yoked together for years, and it doesn't look right that we haven't made it legal, mooed the first ox. Perhaps so, then, lowed the second ox, because it is true that it's better to be married than to burn in hell . . .
A Review of “A User's Guide to Therapy: What to Expect and How you Can Benefit”

Edited by Lora Humphrey Beebe, PhD, PMHNP, BCTamara L. Kaiser, MSW, PhD, is a clinical social worker and marriage and family therapist. She is associate professor in the School of Social Work at th...
A model of ethical decision making by information technology students

This study applies the Theory of Planned Behavior to ethical decision making among Information Technology students. By testing the model using a series of realistic scenarios, we found that student's moral judgment was the most significant predictor of behavioral intention. Applicability to computing education is discussed.
Mechanism of the irreversible inactivation of mouse ornithine decarboxylase by alpha difluoromethylornithine characterization of sequences at the inhibitor and coenzyme binding sites

Mouse ornithine decarboxylase (ODC) was expressed in Escherichia coli and the purified recombinant enzyme used for determination of the binding site for pyridoxal 5'-phosphate and of the residues modified in the inactivation of the enzyme by the enzyme-activated irreversible inhibitor, alpha-difluoromethylornithine (DFMO). The pyridoxal 5'-phosphate binding lysine in mouse ODC was identified as lysine 69 of the mouse sequence by reduction of the purified holoenzyme form with NaB[3H]4 followed by digestion of the carboxymethylated protein with endoproteinase Lys-C, radioactive peptide mapping using reversed-phase high pressure liquid chromatography and gas-phase peptide sequencing. This lysine is contained in the sequence PFYAVKC, which is found in all known ODCs from eukaryotes. The preceding amino acids do not conform to the consensus sequence of SXHK, which contains the pyridoxal 5'-phosphate binding lysine in a number of other decarboxylases including ODCs from E. coli. Using a similar procedure to analyze ODC labeled by reaction with [5-14C]DFMO, it was found that lysine 69 and cysteine 360 formed covalent adducts with the inhibitor. Cysteine 360, which was the major adduct accounting for about 90% of the total labeling, is contained within the sequence -WGPTCDGL(I)D-, which is present in all known eukaryote ODCs. These results provide strong evidence that these two peptides form essential parts of the catalytic site of ODC. Analysis by fast atom bombardment-mass spectrometry of tryptic peptides containing the DFMO-cysteine adduct indicated that the adduct formed in the enzyme was probably the cyclic imine S-(2-(1-pyrroline)methyl)cysteine. This is readily oxidized to S-((2-pyrrole)methyl)cysteine or converted to S-((2-pyrrolidine)methyl)cysteine by NaBH4 reduction. This adduct is consistent with spectral evidence showing that inactivation of the enzyme with DFMO does not entail the formation of a stable adduct between the pyridoxal 5'-phosphate, the enzyme, and the inhibitor.
Application of statistical clustering to mathematical description and control of continuous processes with discrete event output

Statistical clustering is used for the mathematical description of continuous manufacturing processes with discrete event outputs. The resultant mathematical model defines the correspondence between various outcomes of the process and particular regions in the space of process variables. An adaptive version of the clustering model intended for online implementation is presented. Prediction, regime selection, and control procedures, utilizing the clustering model, are formulated. >
Strategic Research to Enable NASA's Exploration Missions Conference

Abstracts are presented from a conference sponsored by the NASA Office of Biological and Physical Research and hosted by NASA Glenn Research Center and the National Center for Microgravity Research on Fluids and Combustion, held in Cleveland, Ohio, June 22-23, 2004. Topics pertained to the behavior of processes and materials in microgravity as well as physiological-biological studies and microgravity effects.
Core-level modeling and frequency prediction for DSP applications on FPGAs

Field-programmable gate arrays (FPGAs) provide a promising technology that can improve performance of many high-performance computing and embedded applications. However, unlike software design tools, the relatively immature state of FPGA tools significantly limits productivity and consequently prevents widespread adoption of the technology. For example, the lengthy design-translate-execute (DTE) process often must be iterated to meet the application requirements. Previous works have enabled model-based, design-space exploration to reduce DTE iterations but are limited by a lack of accurate model-based prediction of key design parameters, the most important of which is clock frequency. In this paper, we present a core-level modeling and design (CMD) methodology that enables modeling of FPGA applications at an abstract level and yet produces accurate predictions of parameters such as clock frequency, resource utilization (i.e., area), and latency. We evaluate CMD's prediction methods using several high-performance DSP applications on various families of FPGAs and show an average clock-frequency prediction error of 3.6%, with a worst-case error of 20.4%, compared to the best of existing high-level prediction methods, 13.9% average error with 48.2% worst-case error. We also demonstrate how such prediction enables accurate design-space exploration without coding in a hardware-description language (HDL), significantly reducing the total design time.
The Human Career: Human Biological and Cultural Origins

The Human Career: Human Biological and Cultural Origins, Richard G. Klein. 2nd edition. Chicago: University of Chicago Press, 1999. 810 pp.