cssi/SciSciGPT-SciSciNet huggingface dataset:
PANEL DISCUSSION : EXPOSURE, REMEDIATION, AND RELATED RESEARCH NEEDS

The panel opened with a request to J. LaVelle (U.S. EPA) to enlarge upon his presentation of a bimodal disposition for the plasma reduction of hexavalent chromium (and subsequent urine concentration) in an occupational group exposed to chromium. He replied that he did not know the size of the population that was exposed, but that the group consisted of workers at a dichromate plant, and the sample size was not very large (1). He added that this distribution does appear to give credence to the theory that there is one reducing agent in plasma that controls the rate of the CrVy redtction. This is in opposition to the thought that many compounds can participate in this reduction, as opposed to one specific rate-determining reduction reaction. R. Wedeen added that it has been stated that the reduction capacity (for chromium) of plasma is 2 ppm and that the remainder of the hexavalent chromium, above that concentration, enters the erythrocyte, to be reduced there. R. Hazen (New Jersey Department of Environmental Protection) was then asked what evidence there is of contact dermatitis in the population of Jersey City. To his knowledge this has not been investigated. Evidence of contact dermatitis from chromium comes from occupationally exposed people and the occupationally exposed have not been investigated in Jersey City, nor to his knowledge, has anyone been tested there. LaVelle added that risk assessment is intended to project into the future, to predict results based on certain exposure scenarios, as opposed to being a description of happenings at a specific site. The question was then asked of Hazen whether risk assessments for chromium have
OP0281 Recent Trends in Medication Usage for the Treatment of Juvenile Idiopathic Arthritis in the United States and the Influence of Tnf Inhibitors

Background The pharmacologic management of JIA has changed dramatically over the last decade with the advent of tumor necrosis factor inhibitors (TNFi), but the impact of TNFi on medication usage in routine clinical practice has not been well-studied. Objectives Using national administrative claims from a large commercial U.S. health insurer, we investigated the use of medications in the treatment of JIA over the last 6 years. We examined medication use by calendar year, as well as medication use before and after new TNFi use among individual patients. Methods Using data from January 2005 through September 2011, we identified children 1 physician diagnosis code consistent with JIA. In the analyses of medication use by year, only subjects with full medical and pharmacy benefits for the entire calendar period were included. Use of TNFi, methotrexate (MTX), non-steroidal anti-inflammatory drugs (NSAIDs), and oral glucocorticoids (GC) was determined using outpatient pharmacy and infusion procedure claims. Significant changes in medication usage over time were evaluated with the Cochran-Armitage test for trend. New users of TNFi were defined by no receipt of any TNFi in the 6 months immediately prior to starting. New TNFi users were required to have a minimum of 6 months of follow-up after starting TNFi, and only the earliest episode of new TNFi use for each individual patient was included. Among prevalent users of NSAIDs and GC, we used paired t-tests to compare the number of filled prescriptions for NSAIDs and the cumulative mean daily GC dose (in prednisone equivalents) in the 6 months before and after new TNFi use. Results Including all years of the study, we identified 3,531 unique individuals with ≥1 JIA diagnosis code. Their median age was 11 years (IQR 7-14) and 64% were female. The proportion of patients receiving TNFi increased during the study period from 8.0% in 2005 to 21.9% in 2011 (p Conclusions TNFi use in the treatment of JIA has increased 2-3 fold over the last 6 years with a concurrent smaller increase in MTX use. New use of TNFi was associated with a reduction in the number of NSAID prescriptions and the mean daily GC dose. The relatively small proportion of patients with recent or concurrent use of MTX around the time of new TNFi use suggests that TNFi may be replacing, rather than complementing, MTX therapy in many patients. Disclosure of Interest M. Mannion: None Declared, F. Xie: None Declared, J. Curtis Grant/research support from: Roche/Genentech, UCB, Janssen, Amgen, Pfizer, BMS, Crescendo, Merk, Lilly, CORRONA, Consultant for: Roche/Genentech, UCB, Janssen, Amgen, Pfizer, BMS, Crescendo, Merck, Lilly, CORRONA, AbbVie, T. Beukelman Grant/research support from: Pfizer, Consultant for: Novartis, Genentech/Roche
Spatial Variation of Pressure in the Lyophilization Product Chamber Part 1: Computational Modeling

The flow physics in the product chamber of a freeze dryer involves coupled heat and mass transfer at different length and time scales. The low-pressure environment and the relatively small flow velocities make it difficult to quantify the flow structure experimentally. The current work presents the three-dimensional computational fluid dynamics (CFD) modeling for vapor flow in a laboratory scale freeze dryer validated with experimental data and theory. The model accounts for the presence of a non-condensable gas such as nitrogen or air using a continuum multi-species model. The flow structure at different sublimation rates, chamber pressures, and shelf-gaps are systematically investigated. Emphasis has been placed on accurately predicting the pressure variation across the subliming front. At a chamber set pressure of 115 mtorr and a sublimation rate of 1.3 kg/h/m2, the pressure variation reaches about 9 mtorr. The pressure variation increased linearly with sublimation rate in the range of 0.5 to 1.3 kg/h/m2. The dependence of pressure variation on the shelf-gap was also studied both computationally and experimentally. The CFD modeling results are found to agree within 10% with the experimental measurements. The computational model was also compared to analytical solution valid for small shelf-gaps. Thus, the current work presents validation study motivating broader use of CFD in optimizing freeze-drying process and equipment design.
Inhibition of SV40 DNA synthesis by camptothecin and neocarzinostatin.

Both camptothecin and neocazinostatin cause 50% inhibition of simian virus 40 DNA synthesis in BSC-1 cells at a drug concentration of 1-0.1 µM. Uniformly prelabeled Form I simian virus 40 DNA is not converted to Form II by 100 µM camptothecin or 10 µM (10 µg/ml) neocarzinostatin, despite extensive drug-induced breakage of cellular DNA at these concentrations. Kinetic experiments examined the fate of replicative intermediates at the onset of inhibition of DNA synthesis. In the presence of 100 µg/ml neocarzinostatin, label proceeds through replicative intermediate molecules and is found largely (>75%) as Form I simian virus 40 DNA. At 100 µM camptothecin, up to 50% of newly made simian virus 40 DNA is found as a Form II-like species.
E-004 intracranial venous hypertension due to severe focal web-like stenosis of the sigmoid sinus associated with contralateral sinus hypoplasia: a new diagnostic entity?

Purpose Regardless of the underlying pathology, elevated intracranial pressure is the end-point of any impairment in either CSF absorption (arachnoid vili) or intracranial venous drainage. Intracranial venous hypertension (ICVH) is an important vascular cause of intracranial hypertension (and its subsequent sequelae) which often has been ignored due to excessive attention to the arterial system and specifically AV shunts. Various anatomical and pathological entities have been described to cause ICVH. For the second time, we present a unique case of severe focal web-like stenosis in the distal sigmoid sinus associated with concurrent hypoplasia of the contralateral transverse sinus (TS) causing a significant pressure gradient and intracranial hypertension. Case Report A 31-month-old boy presented with the chief complaint of progressive vision loss and frequent falls. Physical examination was positive for prominent periorbital veins and decreased bilateral visual acuity. Fundoscopy revealed extensive fluid around the optic nerve and inappreciable cup-to-disc ratio with blurring of the disc margins bilaterally consistent with papilledema. Image Findings MR imaging examination revealed mild to moderate lateral and third ventriculomegaly associated with an empty sella, consistent with increased intracranial pressure. No intracranial/parenchymal, extra-axial mass effect or optic nerve lesion was identified (Figure 1A). DSA demonstrated congenitally hypoplastic right transverse and sigmoid sinuses extending into a small right internal jugular vein. A severe focal web-like stenosis of the distal dominant left sigmoid sinus was observed (Figure 1B). Direct pressure measurement in the dural venous sinuses revealed abnormally elevated pressures proximal to the web-like stenosis and a significant gradient (20 mm Hg) across the stenosis: proximal left internal jugular vein: 12 mmHg, left TS: 40 mmHg, and distal sigmoid sinus: 32 mmHg. Using over-the-wire technique, a self-expanding nitinol stent was placed successfully across the web-like stenosis and sequential overlapping balloon angioplasty was performed successfully. There was immediate improvement in the appearance of the stenosis with a mild residual stenosis and the pressure gradient was immediately and dramatically reduced (Figures 1C and 1D). Summary Isolated venous outflow obstruction leading to intracranial hypertension has been reported before;1 however, the presented case is the second case of a unique morphological venous anomaly, namely a severe focal web-like stenosis occurring in the dominant sigmoid sinus associated with concurrent hypoplasia of the contralateral TS leading to significant pressure gradient and ICVH. Reference Soltanolkotabi M, Rahimi S, Hurley MC, et al. Endovascular correction of an infantile intracranial venous outflow obstruction. Journal of neurosurgery Pediatrics 2013;12:660–663 Disclosures A. Honarmand: None. M. Hurley: None. F. Syed: None. S. Ansari: None. A. Shaibani: None.
[Medical technology: its impact on the physician-patient relationship].

The Nuestra Senora del Remedio Clinic is celebrating the 75th anniversary of the arrival of the San Jose de Gerona order at the clinic. Dr. Vallbona was invited to present a conference which we transcribe in this article, superficially reviewing the problems which may compromise the doctor-patient relationship as well as the rights and responsibilities each member of this relationship has.
Citizen Demand for the Dimensions of Representation

Colorado State Representative Lois Court represents the affluent, educated House District 6, home to doctors, lawyers, and lobbyists in east-central Denver. Although she points out that people are often uninformed about state government, she knows that she must keep up with considerable demand from her constituents regarding policy concerns. This requires a large investment of time learning about topics such as capital punishment and civil unions and responding to any constituents who weigh in on those and other issues. As the size of her e-mail inbox shows, her constituents are monitoring her policy behavior. Rep. Court, a Democrat, follows a straightforward plan for representing the policy concerns of her district, which is about 47% Democrat, 22% Republican, and 31% unaffiliated: she tries to vote the way the majority of constituents from whom she hears wants her to vote. Since she was elected in 2008, she has followed the principle of being guided by a primary obligation to the people in her district. She does not take money from political action committees and does not typically respond to requests from people outside of her district. At times this has led to tension with outside organizations that might be willing to donate to her campaigns. Instead, Rep. Court sees herself as her district's delegate. During the 2013 session, the legislature voted on a series of gun safety bills. She received about 7,500 e-mails and phone calls from around the state telling her how to vote, with the majority of them urging her to vote against the bills. However, the communications from within her district indicated about 2-to-1 support for the gun safety measures. Thus, the choice for Rep. Court was clear. As a delegate for her constituents, she followed through with what the majority in the district (from whom she had heard) wanted. In this chapter, I examine the question of constituent demand for representation by empirically testing the first part of the theoretical framework described in Chapter 2. I show that, in light of my theory, it is not surprising that Lois Court faces considerable demand from her constituents related to policy issues, because wealthy, educated people tend to place a premium on that dimension of representation. My claim from Chapter 2 is that citizens’ views regarding the role of government in their lives drive their demand for representation.
Is structural remodeling in regions governing memory an univocal correlate of memory

Advances in our ability to visualize changes in single neuron morphology during or after training have largely contributed to renew the interest into the structural basis of memory. Nevertheless the idea that structural alterations in memory-specific neural circuits can be univocally considered as correlates of memory needs to be carefully considered in view of evidence showing that a variety of sensorial/motor/emotional stimuli also alter the morphology of neurons in those circuits. The aim of this review is to examine the respective impact of memory vs other forms of experiences in triggering structural plasticity in the rodent brain, the challenge being to disentangle alterations due to the formation of declarative/relational memories from those developing in the same regions in relation to non-memory functions.
Alcohol-Related Visits to US Emergency Departments, 2001-2011.

Aims Alcohol intoxication is a source of significant illness and injury commonly resulting in emergency department (ED) visits. We characterize recent trends in alcohol-related visits to US EDs using nationally representative data. Methods We conducted a retrospective review of data on national ED visits among patients aged 18 years or older with alcohol intoxication between 2001 and 2011 using the National Hospital Ambulatory Medical Care Survey (NHAMCS). Demographic and resource utilization trends in alcohol-related visits were examined. We also assessed ED length of stay (LOS) across the study period, as well as the total hours spent on ED care for alcohol-related complaints. Results Between 2001–2002 and 2010–2011, alcohol-related visits increased from 2,459,748 to 3,856,346 ( P = 0.049). Utilization of resources such as laboratory tests, medications and radiography increased, with the use of advanced imaging (i.e. computed tomography and magnetic resonance imaging) increasing 232.2% ( P < 0.001) from 2001–2002 to 2010–2011. Overall LOS increased 16.1% ( P = 0.028), while LOS among patients admitted to the hospital increased 24.9% ( P = 0.076). Total alcohol-related hours spent in EDs nationwide increased from 5.6 million in 2001 to 11.6 million in 2011, an increase of 108.5% ( P < 0.001) compared with an increase in overall ED hours of 54.0% ( P < 0.001). Conclusion Alcohol-related ED visits are increasing at a greater rate than overall ED visits and represent a growing burden on hospital resources.
Improving Child Peer Adjustment in Military Families Through Parent Training: The Mediational Role of Parental Locus of Control

The current study investigated the mechanisms through which a parenting intervention for military families fosters positive peer adjustment in children. A sample of 336 families with a history of parental deployment enrolled in a randomized controlled trial of the After Deployment Adaptive Parenting Tools (ADAPT) preventive intervention. ADAPT is a 14-week preventive intervention designed to strengthen parenting in military families. The intervention was associated with improvements in mother's and father's parental locus of control (i.e., a more internal locus of control) at a 6-month follow-up assessment while controlling for baseline levels. Mothers' parental locus of control was positively associated with improvements in children's peer adjustment 12 months following the intervention while controlling for baseline peer adjustment. A significant indirect effect revealed that participation in ADAPT resulted in improved 12-month peer adjustment by improving mothers' parental locus of control. Implications for supporting youth resilience to stressors associated with deployment are discussed.
Mastering digital business: How powerful combinations of disruptive technologies are enabling the next wave of digital transformation, by Nicholas D. Evans

During the past three decades, information technology (IT) has become an integral component of all organizations. IT has fundamentally transformed nearly every aspect of businesses and has become t...
Abstract 1145: Overcoming chemoresistance and blocking metastasis in breast cancer by targeting HuR

Patients with metastatic breast cancer have a dismal 5-year survival rate of only 24%. Chemoresistance is another contributor to the high mortality of advanced breast cancer. The RNA-binding protein, Hu antigen R (HuR), is overexpressed at all stages of breast cancer development. Cytoplasmic HuR accumulation correlates with high-grade malignancy, poor distant disease-free survival and serves as a prognostic factor for poor clinical outcome in breast cancer. HuR promotes tumorigenesis by promoting mRNA stability and translation of proteins implicated in proliferation, survival, angiogenesis, invasion, and metastasis. HuR also modulates sensitivity of breast cancer cells to chemotherapy. Taken together, HuR is an emerging target for breast cancer therapy, especially metastatic breast cancer. Using shRNA and CRISPR technologies to modulate HuR expression in breast cancer cells, we found that cells with HuR KD/KO were less invasive and more sensitive to chemotherapy. In an effort to discover small molecules that disrupt the HuR-mRNA interaction and block HuR functions in breast cancer progression, metastasis and chemoresistance, high throughput screening (HTS) was carried out in several chemical libraries (~23,000 compounds) using fluorescence polarization (FP) assay, which identified several initial hits with sub-micromolar inhibitory constants (Ki). Those potential inhbitors were then validated by ALPHA assay (Amplified Luminescent Proximity Homogeneous Assay), confirmed by Surface Plasmon Resonance (SPR). In cell-based assays, top hit KH-3 and its optimized analogs, specifically shortened HuR target mRNA half-lifes and decreased the level of the encoded proteins. Moreover, those compounds inhibited invasion and restored chemosensitivity. qPCR arrays focusing on specific pathways revealed that HuR inhibitors potently upregulated metastatic suppressors and downregulated genes frequently overexpressed in lung metastases. In animal studies, KH-3 not only exhibited potent antitumor efficacy in orthotopic xenografts of breast cancer, but also efficiently blocked experimental metastasis. In conclusion, we identified potent and specific small molecule inhibitors of HuR-mRNA interaction for potential anti-metastatic therapy for breast cancer with HuR overexpression. Citation Format: Xiaoqing Wu, Rebecca Marquez, Shuang Han, Lan Lan, Dan A. Dixon, Jeffrey Aube, Danny R. Welch, Liang Xu. Overcoming chemoresistance and blocking metastasis in breast cancer by targeting HuR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1145. doi:10.1158/1538-7445.AM2017-1145
Scalable Regioselective and Stereoselective Synthesis of Functionalized (E)-4-Iodobut-3-en-1-ols: Gram-Scale Total Synthesis of Fungal Decanolides and Derivatives.

A reliable protocol to synthesize both racemic and chiral (E)-4-iodobut-3-en-1-ols from aldehydes or epoxides, respectively, containing various aromatic and aliphatic substitutions has been established. The utility of these compounds was then demonstrated by providing access to known fungal decanolides as well as novel aromatic macrocycles. The protocol provided a gram-scale route to (−)-aspinolide A and (−)-5-epi-aspinolide A utilizing a catalytic Nozaki–Hiyama–Kishi reaction to close the macrolide in the final step in 65–84% yields.
Amblyceps improcerum , a new sisoroid catfish from Kachin State, Myanmar (Teleostei: Siluriformes: Amblycipitidae)

A new species of amblycipitid catfish is here described from the Indawgyi Lake basin of the Irrawaddy River drainage in Kachin State, Myanmar as Amblyceps improcerum, new species. It can be distinguished from congeners in having a unique combination of the following characters: lower jaw longer than upper; head length 17.4–22.3% SL; head width 13.7–15.2% SL; head depth 9.0–11.7% SL; interorbital distance 31–39% HL; eye diameter 7–10% HL; 37–38 vertebrae; lateral line incomplete; predorsal length 25.5–30.7% SL; smooth posterior margin of pectoral spine; pectoral-fin length 13.5–16.8% SL; pelvic-fin length 9.6–13.4% SL; dorsal-to-adipose distance 25.2–28.7% SL; length of adipose-fin base 19.4–23.3% SL; adipose fin separate from dorsal procurrent caudal-fin rays; preanal length 62.1–66.9% SL; body depth at anus 9.8–12.8% SL; depth of caudal peduncle 10.1–12.6% SL; length of caudal peduncle 21.4–24.0% SL, post-adipose distance 15.8–17.8% SL; weakly-forked caudal fin with short broadly, rounded lobes (length of longest ray 1.3–1.5 times length of median rays); centrally projecting hooks on proximal lepidotrichia of median caudal-fin rays absent.
Contention-aware lock scheduling for transactional databases

Lock managers are among the most studied components in concurrency control and transactional systems. However, one question seems to have been generally overlooked: "When there are multiple lock requests on the same object, which one(s) should be granted first?"Nearly all existing systems rely on a FIFO (first in, first out) strategy to decide which transaction(s) to grant the lock to. In this paper, however, we show that the lock scheduling choices have significant ramifications on the overall performance of a transactional system. Despite the large body of research on job scheduling outside the database context, lock scheduling presents subtle but challenging requirements that render existing results on scheduling inapt for a transactional database. By carefully studying this problem, we present the concept of contention-aware scheduling, show the hardness of the problem, and propose novel lock scheduling algorithms (LDSF and bLDSF), which guarantee a constant factor approximation of the best scheduling. We conduct extensive experiments using a popular database on both TPC-C and a microbenchmark. Compared to FIFO---the default scheduler in most database systems---our bLDSF algorithm yields up to 300x speedup in overall transaction latency. Alternatively, our LDSF algorithm, which is simpler and achieves comparable performance to bLDSF, has already been adopted by open-source community, and was chosen as the default scheduling strategy in MySQL 8.0.3+
Quantification of Material Fluorescence and Light Scattering Cross Sections Using Ratiometric Bandwidth-Varied Polarized Resonance Synchronous Spectroscopy.

Presented herein is the ratiometric bandwidth-varied polarized resonance synchronous spectroscopy (BVPRS2) method for quantification of material optical activity spectra. These include the sample light absorption and scattering cross-section spectrum, the scattering depolarization spectrum, and the fluorescence emission cross-section and depolarization spectrum in the wavelength region where the sample both absorbs and emits. This ratiometric BVPRS2 spectroscopic method is a self-contained technique capable of quantitatively decoupling material fluorescence and light scattering signal contribution to its ratiometric BVPRS2 spectra through the linear curve-fitting of the ratiometric BVPRS2 signal as a function of the wavelength bandwidth used in the PRS2 measurements. Example applications of this new spectroscopic method are demonstrated with materials that can be approximated as pure scatterers, simultaneous photon absorbers/emitters, simultaneous photon absorbers/scatterers, and finally simultaneous phot...
Immunocytochemical Markers for Human Milk Macrophages and Epithelial Cells

Most of the cellular elements obtained from colostrum and early human milk are considered to be macrophages. A varying number of polymorphonuclear leukocytes and a small number of epithelial cells are also present. The morphologic distinction of epithelial cells within the macrophage population and routine staining is extremely difficult. A number of histo-chemical stains (nonspecific esterase, acid phosphatase, oil red, etc.) have been used in the past to further characterize the cellular population of human milk. Distinction, though, between the macrophages and the epithelial cells on a cytochemical basis has proved to be impossible (1).
Gaze Stabilization and the VOR

The vestibulo-ocular reflexes (VORs) serve to keep our image of the world stable as we move. This is accomplished by using signals about head motion from the vestibular apparatus of the inner ear to produce compensatory eye movements that are equal in amplitude and opposite in direction. The semicircular canals detect head rotations, whereas the otolith organs detect head translations and re-orientations relative to gravity. The system is remarkably plastic and can quickly learn to change its output under different sensory and motor conditions. The simplicity and flexibility of the VOR have made it an ideal sensorimotor system to study.
Inferring the Structure of Porous Materials Using Superfluid Helium

The operation of a phase separator for superfluid helium depends on the internal structure of the porous plug. We show how a phase separator apparatus can be used to study the flow through porous materials. This method appears to be better than conventional methods currently in use. Superfluid helium is a preferable test substance over ordinary fluids for two reasons. First, it has nearly zero contact angle for most substrates. Second, the superfluid film insulates the meniscus from surface contamination that causes variations of the contact angle. We present the theory of operation based on the governing equations. The largest term of the pressure balance equations is the jump across the meniscus. The jump is inversely proportional to the hydraulic diameter. We exploit this dependence to find the statistical properties of the hydraulic diameter that are helpful in predicting flows. We find the power spectrum of the hydraulic diameter from the measured data. All the useful probability distributions can be found from the power spectrum. We show how hysteresis loci arise due to the porous structure and discuss the probability distributions necessary to analyze hysteresis loci.
The psychophysics of pictorial perception

Pictorial communication of shape and form is not simply a learned visual language. Whatever processes of learning, if any, underly our ability to perceive represented surfaces’ edges-without which the communication of shape is impossible-in response to outline drawings, probably occurs very early in life in consequence of our normal commerce with spatial objects. Although this probability makes the problems of“learning to see pictures”relatively inaccessible, it simplifies the study of the rules which govern edge- and surface-perception in pictures. The applicability of such rules depends, eventually, on knowing
Neurophysiological signals as predictive translational biomarkers for Alzheimer’s disease treatment: effects of donepezil on neuronal network oscillations in TgF344-AD rats

Translational research in Alzheimer’s disease (AD) pathology provides evidence that accumulation of amyloid-β and hyperphosphorylated tau, neuropathological hallmarks of AD, is associated with complex disturbances in synaptic and neuronal function leading to oscillatory abnormalities in the neuronal networks that support memory and cognition. Accordingly, our recent study on transgenic TgF344-AD rats modeling AD showed an age-dependent reduction of stimulation-induced oscillations in the hippocampus, and disrupted long-range connectivity together with enhanced neuronal excitability in the cortex, reflected in greatly increased expression of high-voltage spindles, an epileptic absence seizure-like activity. To better understand the translational value of observed oscillatory abnormalities in these rats, we examine here the effects of donepezil, an acetylcholine esterase inhibitor clinically approved for AD treatment. Brainstem nucleus pontis oralis stimulation-induced hippocampal oscillations were recorded under urethane anesthesia in adult (6-month-old) and aged (12-month-old) TgF344-AD and wild-type rats. Spontaneous cortical activity was monitored in a cohort of freely behaving aged rats implanted with frontal and occipital cortical electroencephalography (EEG) electrodes. Subcutaneous administration of donepezil significantly augmented stimulation-induced hippocampal theta oscillation in aged wild-type rats and both adult and aged TgF344-AD rats, which have been previously shown to have diminished response to nucleus pontis oralis stimulation. Moreover, in adult TgF344-AD rats, donepezil also significantly increased theta phase-gamma amplitude coupling in the hippocampus during stimulation. However, neither of these effects were significantly changed in adult wild-type rats. Under freely behaving conditions, donepezil treatment had the opposite effect on cortical oscillatory connectivity in TgF344-AD and wild-type rats, and it reduced the occurrence of high-voltage spindle activity in TgF344-AD rats. Together, these results imply that pharmacologically enhancing cholinergic tone with donepezil could partially reverse oscillatory abnormalities in TgF344-AD rats, which is in line with its clinical effectiveness in AD patients. Therefore, our study suggests good translational opportunities for these neurophysiological signals recorded in TgF344-AD rats, and their application could be considered in drug discovery efforts for developing therapies with disease-modifying potential.
Common variable immune deficiency: Dissection of the variable

Starting about 60 years ago, a number of reports appeared that outlined the severe clinical course of a few adult subjects with profound hypogammaglobinemia. Puzzled by the lack of family history and adult onset of symptoms in most, the name "acquired" hypogammaglobinemia was given, but later altered to the current name common variable immune deficiency. Pathology reports remarked on the loss of lymph node architecture and paucity of plasma cells in lymphoid tissues in these subjects. While characterized by reduced serum IgG and IgA and often IgM, and thus classified among the B-cell defects, an increasing number of cellular defects in these patients have been recognized over time. In the early years, severe respiratory tract infections commonly led to a shortened life span, but the wide spread availability of immune globulin concentrates for the last 25 years has improved survival. However, chronic non-infectious inflammatory and autoimmune conditions have now emerged as challenging clinical problems; these require further immunologic understanding and additional therapeutic measures. Recent study of this phenotypic syndrome have provided an increasingly fertile ground for the identification of autosomal recessive and now more commonly, autosomal dominant gene defects which lead to the loss of B-cell development in this syndrome.
Emerging technologies in protein interface engineering for biomedical applications

Protein interactions communicate critical information from the environment into cells to orchestrate functional responses relevant to health and disease. Whereas the natural repertoire of protein interfaces is finite, biomolecular engineering tools provide access to an unlimited scope of potential interactions that can be custom-designed for affinity, specificity, mechanism, or other properties of interest. This review highlights recent developments in protein interface engineering that offer insight into human physiology to inform the design of new pharmaceuticals, with a particular focus on immunotherapeutics. We cover three innovative and translationally promising approaches: (1) reprogramming receptor oligomerization to manipulate signaling pathways; (2) computational protein interface design strategies; and (3) engineering bioorthogonal protein interaction networks.
Rapid inundation of southern Florida coastline despite low relative sea-level rise rates during the late-Holocene

Sediment cores from Florida Bay, Everglades National Park were examined to determine ecosystem response to relative sea-level rise (RSLR) over the Holocene. High-resolution multiproxy analysis from four sites show freshwater wetlands transitioned to mangrove environments 4–3.6 ka, followed by estuarine environments 3.4–2.8 ka, during a period of enhanced climate variability. We calculate a RSLR rate of 0.67 ± 0.1 mm yr−1 between ~4.2–2.8 ka, 4–6 times lower than current rates. Despite low RSLR rates, the rapid mangrove to estuarine transgression was facilitated by a period of prolonged droughts and frequent storms. These findings suggest that with higher and accelerating RSLR today, enhanced climate variability could further hasten the loss of mangrove-lined coastlines, compounded by the reductions in natural flow to the coast caused by water management. Climate variability is nonlinear, and when superimposed on increases in RSLR, can complicate estimated trajectories of coastal inundation for resource management and urban planning. Sea-level rise threatens coastal mangroves, with global consequences for these important blue carbon sinks. Here the authors analyse four Holocene sediment cores from islands in Florida Bay and find that mangroves that comprised the South Florida coastline 4–3000 years ago rapidly transitioned to estuarine conditions, despite low rates of sea-level rise, and propose that their demise was driven by high climate variability.
Confidence intervals for causal effects with invalid instruments by using two‐stage hard thresholding with voting

A major challenge in instrumental variable (IV) analysis is to find instruments that are valid, or have no direct effect on the outcome and are ignorable. Typically one is unsure whether all of the putative IVs are in fact valid. We propose a general inference procedure in the presence of invalid IVs, called two‐stage hard thresholding with voting. The procedure uses two hard thresholding steps to select strong instruments and to generate candidate sets of valid IVs. Voting takes the candidate sets and uses majority and plurality rules to determine the true set of valid IVs. In low dimensions with invalid instruments, our proposal correctly selects valid IVs, consistently estimates the causal effect, produces valid confidence intervals for the causal effect and has oracle optimal width, even if the so‐called 50% rule or the majority rule is violated. In high dimensions, we establish nearly identical results without oracle optimality. In simulations, our proposal outperforms traditional and recent methods in the invalid IV literature. We also apply our method to reanalyse the causal effect of education on earnings.
Educational Program Rankings Are Independently Associated With Residents' Academic Career Trajectory in Neurological Surgery.

Objective Many studies have sought to determine predictors of academic career placement in surgical subspecialities. However, previous research has yet to establish whether the ranking of a surgeon's undergraduate institution or medical school is significantly associated with pursuit of an academic career. The purpose of this study was to investigate these novel factors’ predictive impact on an academic career in the surgical subspeciality of neurosurgery. Factors investigated included undergraduate university rankings, medical school rankings, and residency program rankings. Design Data were retrospectively collected for 884 alumni of Accreditation Council for Graduate Medical Education neurological surgery residency programs. Bivariate analyses were conducted to determine covariates for a logistic regression model, and multivariate analysis was performed with 13 covariates to determine which factors were independently associated with academic career trajectory. Results In multivariate analysis, factors that were independently associated with an academic career in neurological surgery included having 1 year or more of protected research time during residency (odds ratio [OR] =1.96, p = 0.020), attending a “top” undergraduate university (OR =1.88, p = 0.00033), attending a “top” research medical school (OR = 1.53, p = 0.031) attending a residency program affiliated with a “top” research medical school (OR = 1.78, p = 0.012), possessing a Master of Science (OR = 3.46, p = 0.00097), or Doctor of Philosophy (OR = 2.05, p = 0.0019) degree, and completing a clinical fellowship (OR = 2.56, p = 1.90 × 10−8). Conclusions Our study establishes 3 novel factors for predicting residents’ choice of pursuing an academic career in neurological surgery, namely undergraduate university rank, medical school rank, and completing residency at a program affiliated with a “top” research medical school. Such findings reinforce the notion that educational and training environments are key in shaping the career trajectory of future academic surgical subspecialists.
Vehicle-to-Vehicle In-Route Wireless Charging System

This paper presents a method for electric vehicles (EVs) to charge their battery while on a trip, without the need of an expensive change in infrastructure. The proposed method charges EVs while en route from another vehicle, which will be referred to as vehicle-to-vehicle recharging (VVR). The aim of this system is to bring an innovative way for EVs to charge their battery without getting off route on a highway. The electric vehicle can request such a service from a designated charger vehicle on demand and receive electric power wirelessly while en route. The vehicles that provide energy (charger vehicles) through wireless power transfer (WPT) only need to be semi-autonomous in order to engage/disengage during a trip. The state-of-the-art presented in this paper focuses on infrastructures aimed to reduce the burden of charging EVs. Furthermore, modeling, analysis, and simulation is presented to validate the feasibility of the proposed system.
Hedgehog signaling controls progenitor differentiation timing

Hedgehog (Hh) signaling acts as a developmental morphogen that contributes to the diversification of cell fates and tissue patterning in multiple embryonic contexts, as well as regulating the proliferation of adult tissue stem cells1-9. Here, we report a novel function of Hh signaling GLI transcription factors (TFs) in directly governing the timing of cellular differentiation, independent of a role in specification or proliferation. Disruption of active Hh signaling in the embryo resulted in reduced expression of a progenitor-specific transcription factor network and the inappropriate activation of cardiac differentiation-specific gene expression programs. Expression of the activating Hh transcription factor, GLI1, a marker and effector of active Hh signaling, is correlated with stem and progenitor states during the differentiation of all three germ layers in mouse and human. Transient induction of GLI1 in mouse embryonic stem cell (mESC)-derived cardiac and neural progenitors delayed the onset of the cardiomyocyte and neuron differentiation programs, respectively, while activating progenitor-specific gene expression. GLI1 expression in cardiac progenitors promoted a shift in chromatin accessibility towards a progenitor-like profile at distal regulatory elements near Hh-dependent genes. Manipulating the balance of active to repressive GLI TF predominance unveiled a molecular switch that determined the activity patterns of progenitor-specific distal cis-regulatory elements in vitro and in vivo. Overriding this switch through forced expression of a repressive GLI TF in cardiac progenitors in vivo caused precocious cardiomyocyte differentiation and Congenital Heart Disease (CHD). Our data suggest that a GLI TF switch at distal regulatory elements maintains progenitor cell status and inhibits premature differentiation through the activation and maintenance of a progenitor-specific regulatory network, thus controlling progenitor differentiation timing. We propose a novel molecular paradigm for progenitor maintenance in diverse cellular contexts by signal-dependent TFs with implications for organ development, regenerative potential, and Hh-driven cancers.
Secure Event-Triggered Distributed Kalman Filters for State Estimation over Wireless Sensor Networks.

In this paper, we analyze the adverse effects of cyber-physical attacks as well as mitigate their impacts on the event-triggered distributed Kalman filter (DKF). We first show that although event-triggered mechanisms are highly desirable, the attacker can leverage the event-triggered mechanism to cause non-triggering misbehavior which significantly harms the network connectivity and its collective observability. We also show that an attacker can mislead the event-triggered mechanism to achieve continuous-triggering misbehavior which not only drains the communication resources but also harms the network's performance. An information-theoretic approach is presented next to detect attacks on both sensors and communication channels. In contrast to the existing results, the restrictive Gaussian assumption on the attack signal's probability distribution is not required. To mitigate attacks, a meta-Bayesian approach is presented that incorporates the outcome of the attack detection mechanism to perform second-order inference. The proposed second-order inference forms confidence and trust values about the truthfulness or legitimacy of sensors' own estimates and those of their neighbors, respectively. Each sensor communicates its confidence to its neighbors. Sensors then incorporate the confidence they receive from their neighbors and the trust they formed about their neighbors into their posterior update laws to successfully discard corrupted information. Finally, the simulation result validates the effectiveness of the presented resilient event-triggered DKF.
Amelioration of Murine Macrophage Activation Syndrome by Monomethyl Fumarate in Both a Heme Oxygenase 1-Dependent and Heme Oxygenase 1-Independent Manner.

OBJECTIVE Macrophage activation syndrome (MAS) is characterized by increased serum levels of ferritin and heme oxygenase 1 (HO-1), and yet no known function is ascribed to these molecules in MAS. Because HO-1 is antiinflammatory, we hypothesized that pharmacologic activation of HO-1 could ameliorate MAS disease activity. Dimethyl fumarate (DMF), a treatment approved by the US Food and Drug Administration for multiple sclerosis, activates HO-1. Monomethyl fumarate (MMF) is the active metabolite of DMF. We therefore evaluated whether MMF could elicit HO-1-dependent therapeutic improvements in a murine model of MAS. METHODS We induced MAS by repeated activation of Toll-like receptor 9 (TLR-9) in wild-type and myeloid-specific HO-1-deficient mice. MMF was administered twice daily to test its efficacy. We assessed organ weights, serum cytokine levels, histologic features of the spleen and liver tissue, and complete blood cell counts to evaluate disease activity. Statistical testing was performed using Student's t-test or by 2-way analysis of variance as appropriate. RESULTS The presence of HO-1 was required for the majority of TLR-9-induced interleukin-10 (IL-10). IL-10 production in TLR-9-induced MAS was found to correlate with the myeloid-HO-1 gene dose in myeloid cells (P < 0.001). MMF treatment increased the levels of HO-1 in splenic macrophages by ~2-fold (P < 0.01), increased serum levels of IL-10 in an HO-1-dependent manner in mice with TLR-9-induced MAS (P < 0.005), and improved multiple disease parameters in both an HO-1-dependent and HO-1-independent manner. CONCLUSION TLR-9-induced production of IL-10 is regulated by HO-1 activity both in vitro and in vivo. Therapeutic enhancement of the HO-1/IL-10 axis in a murine model was able to significantly ameliorate MAS disease activity. These results suggest that HO-1 may be viable as a MAS therapeutic target, and treatment with DMF and MMF should be considered in future investigations of MAS therapy.
Social Media, Privacy, and the Employment Relationship: The American Experience

This article posits that privacy issues arising in the United States from the use of social media and the employment relationship are similar to those that have arisen around the world. It suggests, however, that the patchwork of governing legal claims arising under different laws in different jurisdictions may be unique. After a brief introduction, the second section describes the recent passage of legislation in several states that may protect the privacy of job applicants’ passwords to social media sites. The third section describes the various claims employees may bring under the federal Electronic Communications Privacy Act, in tort for invasion of privacy, pursuant to the Fourth Amendment, or to enforce just cause provisions in collective bargaining agreements. The fourth section describes protection from overbroad discovery of social media when employers and former employees are involved in litigation. The article concludes by assessing the likelihood of further legal reform.
A UCSD view on replication and reproducibility for CPS & IoT

Reproducibility and replicability (R&R) are important for research. Many communities are beginning efforts to reward, incentivize, and highlight projects as a motive to adopt R&R practices. This is clearly a good direction - we should all aim to make our research sound, replicable, and reproducible. Yet, this involves a lot of effort to document, debug, and generally make the systems that we build more usable. Interfacing with the Physical world and building custom Things exacerbates these challenges. Therein lies the dilemma: how does the CPS/IoT community reward and incentivize R&R efforts? This paper looks into the question of R&R in CPS/IoT. We survey efforts in other fields spanning computing to healthcare and highlight similarities and differences to CPS/IoT. We then discuss several exemplar CPS/IoT projects related to UCSD's research and highlight the R&R efforts in these projects, the potential ways that they could be improved, and best practices. We finish with recommendations and insights for R&R tailored to the CPS/IoT community.