cssi/SciSciGPT-SciSciNet huggingface dataset:
Insolation and greenhouse gases drove Holocene winter and spring warming in Arctic Alaska

Abstract Global surface temperature changes and their drivers during the Holocene Epoch remain controversial. Syntheses of proxy data indicate that global mean annual temperature declined from the mid-Holocene until the Pre-industrial Era, a trend linked to decreasing Northern Hemisphere summer insolation. In contrast, global climate models simulate increasing mean annual temperatures driven by retreating ice sheets and increasing greenhouse gas concentrations. This proxy-model disagreement may originate from a warm season bias in Northern Hemisphere proxy reconstructions, highlighting the need for new proxies that quantify cold season temperature, especially in Arctic regions that were devoid of continental ice sheets during the Holocene. Here, we present a new 16,000-year winter-spring temperature reconstruction derived from the unsaturation ratio of alkenones ( U 37 K ) in a continuous sedimentary sequence from Lake E5, northern Alaska. We employ a thermodynamic lake model to convert alkenone-inferred lake temperatures into winter-spring air temperature anomalies and we contextualize our proxy reconstruction with climate model output from the region. Our reconstruction shows that winter-spring temperatures warmed rapidly during the deglaciation at 16 and 14 thousand years before present and continued to warm gradually throughout the middle and late Holocene (0.12–0.28 °C/thousand years) in concert with regional sea surface temperature and sea ice records. Our results are consistent with climate model simulations and we attribute Holocene warming to rising winter-spring insolation, radiative forcing from rising greenhouse gas concentrations and regional feedbacks. Our reconstructed cold season warming equaled or exceeded summer cooling according to a regional synthesis of temperature records, suggesting that seasonal biases in temperature reconstructions may account for proxy-model disagreements in Holocene temperature trends from Eastern Beringia.
Cryo-electron tomography of the herpesvirus procapsid reveals interactions of the portal with the scaffold and a shift on maturation

Herpes simplex virus type 1 (HSV-1) packages its genome via the portal protein, pUL6, a dodecameric ring at one of the capsids twelve vertices. While the portal has been visualized in mature capsids, we aimed to describe it in procapsids to elucidate its role in assembly and maturation. Using cryo-electron tomography, we compared procapsids and empty mature capsids (A-capsids) by subtomogram averaging. The portal is located on the interior surface with its narrower end facing outwards in contact with the capsid shell. The portal is embedded in the underlying scaffold, consistent with assembly initiating on a portal-scaffold complex. Maturation involves angularization of the capsid shell, with an accompanying outward movement of the vertices. In A-capsids, the portal translocates further than the surrounding capsomers, enhancing and presumably strengthening its contacts with the capsid shell. We also found a density overlying and offset from the portal vertex corresponding to the expected location of the terminase, the DNA packaging motor.
Differential Expression of Viral Transcripts From Single-Cell RNA Sequencing of Moderate and Severe COVID-19 Patients and Its Implications for Case Severity

With steady increase of new COVID-19 cases around the world, especially in the United States, health care resources in areas with the disease outbreak are quickly exhausted by overwhelming numbers of COVID-19 patients. Therefore, strategies that can effectively and quickly predict the disease progression and stratify patients for appropriate health care arrangements are urgently needed. We explored the features and evolutionary difference of viral gene expression in the SARS-CoV-2 infected cells from the bronchoalveolar lavage fluids of patients with moderate and severe COVID-19 using both single cell and bulk tissue transcriptome data. We found SARS-CoV-2 sequences were detectable in 8 types of immune related cells, including macrophages, T cells, and NK cells. We first reported that the SARS-CoV-2 ORF10 gene was differentially expressed in the severe vs. moderate samples. Specifically, ORF10 was abundantly expressed in infected cells of severe cases, while it was barely detectable in the infected cells of moderate cases. Consequently, the expression ratio of ORF10 to nucleocapsid (N) was significantly higher in severe than moderate cases (p = 0.0062). Moreover, we found transcription regulatory sequences (TRSs) of the viral leader sequence-independent fusions with a 5' joint point at position 1073 of SARS-CoV-2 genome were detected mainly in the patients with death outcome, suggesting its potential indication of clinical outcome. Finally, we identified the motifs in TRS of the viral leader sequence-dependent fusion events of SARS-CoV-2 and compared with that in SARS-CoV, suggesting its evolutionary trajectory. These results implicated potential roles and predictive features of viral transcripts in the pathogenesis of COVID-19 moderate and severe patients. Such features and evolutionary patterns require more data to validate in future.
Laparotomy Closure: A Review of Available Education Training Models.

Introduction As studies continue to provide advanced knowledge concerning abdominal wall closure after laparotomy, there have been many improvements in surgical techniques and recommended closure materials. However, there continues to be a high rate of incisional hernias following exploratory laparotomies. The goal of this review is to provide a comprehensive assessment of available educational models for laparotomy closure. Material and methods A comprehensive literature review was made using PubMed, Cochrane, and NCBI MeSH databases to find the most relevant articles associated with various abdominal closure models using specific keywords. Results Human cadaver, animal, synthetic, and virtual reality models were reviewed. Strengths and limitations of each model were described. Conclusion Each model has practical benefits in its ability to mimic in vitro anatomy and the experiential similarities to actual laparotomy closure. However, there are also limitations and potential cost-prohibitive factors for individual models. Overall, while there have been some advances in synthetic and virtual models, human cadaver and porcine models remain the most similar to human abdominal wall closures.
Abstract 113: Effects of Anticoagulation and Thrombolytic Therapy in a Porcine Model of Prolonged Out-of-hospital Cardiac Arrest Treated with ECPR

Background: Extracorporeal cardiopulmonary resuscitation (ECPR) has been used in patients with refractory out-of-hospital cardiac arrest (OHCA). However, recovery of organ function and survival are...
ONE-ELECTRON SPECTRAL WEIGHT OF DOPED MOTT INSULATORS IN GAUGE FIELD THEORY APPROACH

The electron spectral weight of doped Mott insulators based on the two-dimensional slave boson gauge field theory is studied. The vertex correction with static gauge field is calculated in the second order perturbation theory. The vertex correction is found to be singular at low energy and requires non-perturbative treatments.
Path to a profession: How a physician assistant becomes a physician assistant

This pilot study, through the application of phenomenological methodology, considered the physician assistant (PA) profession as a "lived experience" in an attempt to understand how these medical practitioners end up on the PA path and what keeps them there. Additionally, the researchers focused on understanding why specific individuals gravitate towards the PA education option. Major themes that developed during the interviews with eight PAs included personal unfamiliarity with the PA profession during the first two decades of life, the decision to pursue PA training while in undergraduate studies, assuming roles often considered MD/DO specific and the subsequent patient confusion with the difference between a PA and an MD/DO, and significant work satisfaction resulting in the lack of desire to change profession. These themes, especially personal unfamiliarity with the PA profession and patient confusion with the difference between a PA and an MD/DO, promotes an environment that perpetuates a lack of understanding about PAs, particularly in younger (e.g., pre-collegiate) individuals. Considering the consequences of this knowledge gap along with the equivocal validity of a pilot study and the potentially subjective nature of phenomenology, the researchers recommend further investigations, both quantitative and qualitative, to either confirm or repudiate these findings.
MEDIA EXPOSURE AND SYMPATHETIC NERVOUS SYSTEM REACTIVITY PREDICT PTSD SYMPTOMS AFTER THE BOSTON MARATHON BOMBINGS

Background: Terrorist attacks have been shown to precipitate posttraumatic stress disorder (PTSD) symptomatology in children and adolescents, particularly among youths with high exposure to media coverage surrounding such events. Media exposure may be particularly likely to trigger PTSD symptoms in youths with high physiological reactivity to stress or with prior psychopathology or exposure to violence. We examined the interplay between media exposure, preattack psychopathology, autonomic nervous system (ANS) reactivity, and prior violence exposure in predicting PTSD symptom onset following the terrorist attack at the 2013 Boston Marathon. Methods: A community sample of 78 adolescents (mean age = 16.7 years, 65% female) completed a survey about the bombings, including media exposure to the event and PTSD symptoms. All respondents participated in a study assessing psychopathology prior to the attack, and sympathetic and parasympathetic reactivity to a laboratory-based stressor was assessed in a subset (N = 44) of this sample. We examined the associations of media exposure, ANS reactivity, preattack psychopathology, and prior violence exposure with onset of PTSD symptoms related to the bombings. Results: Media exposure, preattack psychopathology, and prior violence exposure were associated with PTSD symptoms. Moreover, media exposure interacted with sympathetic reactivity to predict PTSD symptom onset, such that adolescents with lower levels of sympathetic reactivity developed PTSD symptoms only following high exposure to media coverage of the attack. Conclusions: We provide novel evidence that physiological reactivity prior to exposure to an unpredictable traumatic stressor predicts PTSD symptom onset. These findings have implications for identifying youths most vulnerable to PTSD following wide-scale trauma. Depression and Anxiety 31:551–558, 2014. C � 2014 Wiley Periodicals, Inc.
AdS 4 /CFT 3 squashed, stretched and warped

We use group theoretic methods to calculate the spectrum of short multiplets around the extremum of = 8 gauged supergravity potential which possesses = 2 supersymmetry and SU(3) global symmetry. Upon uplifting to M-theory, it describes a warped product of AdS4 and a certain squashed and stretched 7-sphere. We find quantum numbers in agreement with those of the gauge invariant operators in the = 2 superconformal Chern-Simons theory recently proposed to be the dual of this M-theory background. This theory is obtained from the U(N) × U(N) theory through deforming the superpotential by a term quadratic in one of the superfields. To construct this model explicitly, one needs to employ monopole operators whose complete understanding is still lacking. However, for the U(2) × U(2) gauge theory we make a proposal for the form of the monopole operators which has a number of desired properties. In particular, this proposal implies enhanced symmetry of the U(2) × U(2) ABJM theory for k = 1,2; it makes its similarity to and subtle difference from the BLG theory quite explicit.
Adenosine myocardial perfusion single photon emission computed tomographic stress testing 24-72 h after uncomplicated myocardial infarction.

Safety of performing adenosine myocardial perfusion stress testing as early as 24 h after acute uncomplicated myocardial infarction is not known. We evaluated 31 (14 females and 17 males, average age 72, range 46–89 years) consecutive patients with uncomplicated myocardial infarction, who underwent adenosine myocardial perfusion stress imaging, 24–72 h after infarction for risk stratification. Adenosine was infused at a rate of 140 μg/kg/min for 6 min. Twenty patients were presented with non-ST-elevation myocardial infarction. Eleven patients were admitted with acute ST-elevation myocardial infarction. Patients were monitored for signs of complication during and immediately after the stress test. The average time from admission to performance of stress tests was 51 ± 19 h, ranging from the minimum of 24 h to maximum 72 h. No complications related to adenosine infusion were detected. In conclusion, our data suggest that a further large study of early adenosine myocardial perfusion SPECT imaging may be safe in a carefully selected group of patients after uncomplicated myocardial infarction.
Technology and Privacy: The New Landscape

From the Publisher: Privacy is the capacity to negotiate social relationships by controlling access to information about oneself. As laws, policies, and technological developments increasingly structure our relationships with social institutions, privacy faces new threats and new opportunities. The essays in this book provide a new conceptual framework for analyzing and debating privacy policy and for designing and developing information systems. The authors are international experts in the technical, economic, and political aspects of privacy; the book's particular strengths are its synthesis of these three aspects and its treatment of privacy issues in Canada and in Europe as well as in the United States.
MDN: A Web Portal for Network Analysis of Molecular Dynamics Simulations

We introduce a web portal that employs network theory for the analysis of trajectories from molecular dynamics simulations. Users can create protein energy networks following methodology previously introduced by our group, and can identify residues that are important for signal propagation, as well as measure the efficiency of signal propagation by calculating the network coupling. This tool, called MDN, was used to characterize signal propagation in Escherichia coli heat-shock protein 70-kDa. Two variants of this protein experimentally shown to be allosterically active exhibit higher network coupling relative to that of two inactive variants. In addition, calculations of partial coupling suggest that this quantity could be used as part of the criteria to determine pocket druggability in drug discovery studies.
Orthogonal wave propagation of epileptiform activity in the planar mouse hippocampus in vitro.

Summary Purpose: In vitro brain preparations have been used extensively to study the generation and propagation of epileptiform activity. Transverse and longitudinal slices of the rodent hippocampus have revealed various patterns of propagation. Yet intact connections between the transverse and longitudinal pathways should generate orthogonal (both transverse and longitudinal) propagation of seizures involving the entire hippocampus. This study utilizes the planar unfolded mouse hippocampus preparation to reveal simultaneous orthogonal epileptiform propagation and to test a method of arresting propagation. Methods: This study utilized an unfolded mouse hippocampus preparation. It was chosen due to its preservation of longitudinal neuronal processes, which are thought to play an important role in epileptiform hyperexcitability. 4-Aminopyridine (4-AP), microelectrodes, and voltage-sensitive dye imaging were employed to investigate tissue excitability. Key Findings: In 50-μm 4-AP, stimulation of the stratum radiatum induced transverse activation of CA3 cells but also induced a longitudinal wave of activity propagating along the CA3 region at a speed of 0.09 m/s. Without stimulation, a wave originated at the temporal CA3 and propagated in a temporal–septal direction could be suppressed with glutamatergic receptor antagonists. Orthogonal propagation traveled longitudinally along the CA3 pathway, secondarily invading the CA1 region at a velocity of 0.22 ± 0.024 m/s. Moreover, a local lesion restricted to the CA3 region could arrest wave propagation. Significance: These results reveal a complex two-dimensional epileptiform wave propagation pattern in the hippocampus that is generated by a combination of synaptic transmission and axonal propagation in the CA3 recurrent network. Epileptiform propagation block via a transverse selective CA3 lesion suggests a potential surgical technique for the treatment of temporal lobe epilepsy.
The allelic context of the C797S mutation acquired upon treatment with third generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies

Purpose A secondary EGFR mutation, T790M, is the most common resistance mechanism in EGFR-mutant adenocarcinomas that have progressed on erlotinib. Third-generation EGFR inhibitors capable of inhibiting mutant EGFR with T790M produce responses in nearly two thirds of patients. However, acquired resistance mechanisms in patients treated with these drugs are yet to be described. Experimental design To study acquired resistance to third-generation EGFR inhibitors, T790M-positive cells derived from an erlotinib-resistant cancer were made resistant to a third-generation TKI and then characterized using cell and molecular analyses. Results Cells resistant to a third-generation TKI acquired an additional EGFR mutation, C797S, which prevented suppression of EGFR. Our results demonstrate that the allelic context in which C797S was acquired may predict responsiveness to alternative treatments. If the C797S and T790M mutations are in trans, cells will be resistant to third-generation EGFR TKIs, but will be sensitive to a combination of first- and third-generation TKIs. If the mutations are in cis, no EGFR TKIs alone or in combination can suppress activity. If C797S develops in cells wild-type for T790 (when third-generation TKIs are administered in the first-line setting), the cells are resistant to third-generation TKIs, but retain sensitivity to first-generation TKIs. Conclusions Mutation of C797S in EGFR is a novel mechanism of acquired resistance to third-generation TKIs. The context in which the C797S develops with respect to the other EGFR alleles affects the efficacy of subsequent treatments.
Specious Bedfellows: Ethnicity, Animality, and the Intimacy of Slaughter in Moby-Dick

Anxious to “make [his] Self an man,” Maine youth Joseph Loring swore off the lure of the California goldfields and shipped out on a New Bedford whaling vessel a month prior to Moby-Dick’s publication in the fall of 1851. A year and a half later, he proudly wrote to his mother that he had “struck 5 whales and ha[d] not gotten [his] head smashed yet.”1 In fact, he was now so much less “green” that he could as readily “go on to a whale as go over the hill of an evening or escort a school marm to her place of abode.” Assuring her that his labors on board were equally serene, he gladly reported that his ship “is scelibrated for the harmony in which here officers and aftergard live [and] there has not bin a hard word be twine the officers or the Stewers the 14 months that wee have bin to gather.” Yet such sentimental scenes of domestic bliss appear as a cover for his unavoidable worry that, “Still an unlucky blow may make Sauce Pans out of me.” Torn between portraying his struggle with whales as manly graciousness and non-hierarchical camaraderie or as brutally dangerous sport against a worthy adversary, Loring hastily states the inescapable fact of his utter dependence on sperm whales in an aphorism worthy of Ishmael: “Yet by them I live or by them I die.” In regaling his family with news of his voyage, Joseph Loring suggests that an apparatus of affect and domestic bliss mitigates his overwhelming dependence on creatures of the sea for his existence and earnings. His emphasis on the sympathetic feeling between crewmembers and his own vulnerability to sperm whales runs counter to dominant characterizations of the harvesting of whales and challenges accepted interpretations of the industry’s most famous literary tribute, Moby-Dick. Nineteenth-century whaling has been praised as the paradigmatic enterprise of masculine vigor, built of “exposure, privation, and danger, in comparison with which other field-sports are tame, safe, and
A mixed-oxide assembly design for rapid disposition of weapons plutonium in pressurized water reactors

We have created a new mixed-oxide (MOX) fuel assembly design for standard pressurized water reactors (PWRs). Design goals were to maximize the plutonium throughput while introducing the lowest pert...
Cloning, organization, and expression of the bioluminescence genes of Xenorhabdus luminescens.

The lux genes of Xenorhabdus luminescens, a symbiont of the nematode Heterorhabditis bacteriophora, were cloned and expressed in Escherichia coli. The expression of these genes in E. coli was qualitatively similar to their expression in X. luminescens. The organization of the genes is similar to that found in the marine luminous bacteria. Hybridization studies with the DNA that codes for the two subunits of luciferase revealed considerable homology among all of the strains of X. luminescens and with the DNA of other species of luminous bacteria, but none with the nonluminous Xenorhabdus species. Gross DNA alterations such as insertions, deletions, or inversions do not appear to be involved in the generation of dim variants known as secondary forms. Images
A random effects four-part model, with application to correlated medical costs

In this paper we propose a four-part random effects model, with application to correlated medical cost data. Four joint equations are used to model respectively: (1) the probability of seeking medical treatment, (2) the probability of being hospitalized (conditional on seeking medical treatment), and the actual amount of (3) outpatient and (4) inpatient costs. Our model simultaneously takes account of the inter-temporal (or within-cluster) correlation of each patient and the cross-equation correlation of the four equations, by means of joint linear mixed models and generalized linear mixed models. The estimation is accomplished by the high-order Laplace approximation technique in Raudenbush et al. [Raudenbush, S.W., Yang, M., Yosef, M., 2000. Maximum likelihood for generalized linear models with nested random effects via high-order, multivariate Laplace approximation. Journal of Computational and Graphical Statistics 9, 141-157] and Olsen and Schafer [Olsen, M.K., Schafer, J.L., 2001. A two-part random effects model for semicontinuous longitudinal data. Journal of the American Statistical Association 96, 730-745]. Our model is used to analyze monthly medical costs of 1397 chronic heart failure patients from the clinical data repository (CDR) at the University of Virginia.
Quantification and comparison of telovelar and transvermian approaches to the fourth ventricle.

OBJECTIVE To quantify the exposure to the fourth ventricle obtained with the telovelar and transvermian approaches. METHODS The telovelar, with and without C1 posterior arch removal, and transvermian approaches were performed on six cadaveric heads. The area of surgical exposure was calculated from triangles formed by defined anatomic points. A robotic microscope was used to determine the "angle of approach" for the same points. RESULTS The maximal allowable vertical angle of attack to the obex of the fourth ventricle was significantly greater with the telovelar approach than with the transvermian approach (P < 0.002), but there was no difference at the rostral fourth ventricle. The maximal allowable horizontal angle of attack at the level of the obex, Luschka, and rostral fourth ventricle was significantly greater with the telovelar than with the transvermian approach (P < 0.001). Removal of the C1 posterior arch with the telovelar approach significantly increased the vertical angle of approach to the obex (P < 0.001) and rostral aspect of the fourth ventricle (P = 0.005) compared with the telovelar alone. The telovelar approach with C1 arch removal offered a larger working area than the transvermian approach (P < 0.001). CONCLUSION Except for the vertical angle to the rostral aspect of the fourth ventricle, the telovelar approach provides greater angle of exposure in all planes than the transvermian approach. Removal of the C1 posterior arch obviates this sole advantage of the transvermian approach. The telovelar approach offers a corridor through noneloquent arachnoid planes and a safe and capacious working environment.
The Prognosis in Aortic Dissection (Dissecting Aortic Hematoma or Aneurysm)

Between 1945 and 1961 50 patients with aortic dissection were seen at the Mayo Clinic. Survival information for prognostic purposes was available in 40 patients and revealed that more than half of the patients were dead within a week. Of 15 patients who survived the acute phase (2 weeks) more than half were dead within a year. The cause of death was determined by necropsy in 24 patients and 22 died of external rupture of the dissecting aneurysm. In 11 patients a site of re-entry in the dissection was found and in all of these patients external aortic rupture had occurred also. The surgical approach to the treatment of aortic dissection is discussed in the light of these findings. The relationship of the location of the primary tear, blood pressure, and the age of the patient to prognosis is reviewed.
Occurrence of ether-containing inositol phospholipids in bovine erythrocytes.

Abstract Several proteins including bovine erythrocyte acetylcholinesterase are anchored in the membrane through glycoinositol phospholipids containing an alkyl linkage at the sn -1 position of the glycerol. However, the existence of 1-alkyl-2-acyl- sn -glycero-3-phosphoinositol (alkylacyl-GPI) in biological systems has not been demonstrated. In this study, we identified the presence of alkylacyl-GPI in bovine erythrocytes by the following criteria: (1) TLC-Rf value, (2) radyllyso-GPI was produced after phospholipase A2 treatment of the diradyl-GPI, and (3) benzoate derivatives of alkylacylglycerols produced by phospholipase C hydrolysis of diradyl-GPI had the same retention time as that of authentic alkylacylglycerobenzoates on normal-phase HPLC. Diradyl-GPI consisted of 5–10% alkylacyl-GPI. Reverse-phase HPLC analysis of alkylacylglycerobenzoates derived from bovine erythrocyte alkylacyl-GPI showed a multiplicity of species with 18:0–20:4 (11.7%), 16:0–18:1 + 18:0–18:2 (34.9%), and 18:0–18:1 (19.4%) being the major components. Composition of alkyl chains of alkylacyl-GPI from bovine erythrocytes was similar to the reported value for alkylacylglycerols isolated from the glycoinositol phospholipid anchor of bovine erythrocyte acetylcholinesterase. Based on these results, we suggest that alkylacyl-GPI serves as a precursor for the glycoinositol phospholipid of the anchored proteins.
Transcatheter desiccation of the canine left ventricle using radiofrequency energy: A pilot study

Abstract Catheter ablation of cardiac tissue by means of direct-current electrical energy is associated with several complications. We assessed the efficacy and safety of closed-chest catheter desiccation of the left ventricular myocardium with microbipolar radiofrequency (RF) energy (750 kHz) in five dogs. The unipolar configuration was used with RF energy delivered between the tip electrode of a standard No. 7F tripolar catheter in the left ventricle and an external patch electrode on the left lateral chest wall. A single application with different RF energy settings (100 J, 200 J, and 300 J) was delivered to three individual endocardial sites of the left ventricle. Ventricular tachycardia or fibrillation was not observed during energy application and 24 hours after abiation, as assessed by a Holter recording. There was no damage to the electrode catheter. Dogs were killed on the fifth day. Pathology showed well-delineated ovold or round-shaped coagulation necrosis at the ablation sites. Microscopic findings consisted of circumscribed areas of necrosis surrounded by a zone of fibroblastic and mononuclear proliferation. In conclusion, catheter abiation of the ventricular myocardium with RF energy is an apparently safe procedure and can effectively produce discrete areas of injury without destruction of surrounding uninvolved myocardium. This method offers potential clinical utillty for catheter ablation of refractory sustained ventricular tachycardia.
14N chemical shifts and quadrupole coupling constants of inorganic nitrates.

The isotropic chemical shift and the nuclear quadrupole coupling constant for (14)N were obtained for 14 inorganic nitrates by solid-state MAS NMR measurements at two different field strengths, 9.4 and 11.7 T. The compounds studied were polycrystalline powders of AgNO(3), Al(NO(3))(3), Ba(NO(3))(2), Ca(NO(3))(2), CsNO(3), KNO(3), LiNO(3), Mg(NO(3))(2), NaNO(3), Pb(NO(3))(2), RbNO(3), Sr(NO(3))(2), Th(NO(3))(4)center dot4H(2)O, and UO(2)(NO(3))(2)center dot3H(2)O. Even though the spectra show broadening due to (14)N quadrupole interactions, linewidths of a few hundred hertz and a good signal-to-noise ratio were achieved. From the position of the central peaks at the two fields, the chemical shifts and the nuclear quadrupole coupling constants were calculated. The chemical shifts for all compounds studied range from 282 to 342 ppm with respect to NH(4)Cl. The nuclear quadrupole coupling constants range from 429 kHz for AgNO(3) to 993 kHz for LiNO(3). These data are compared with those available in the literature.
Antibody Drug Conjugates: Design and Selection of Linker, Payload and Conjugation Chemistry

Antibody drug conjugates (ADCs) have emerged as an important pharmaceutical class of drugs designed to harness the specificity of antibodies with the potency of small molecule therapeutics. The three main components of ADCs are the antibody, the linker, and the payload; the majority of early work focused intensely on improving the functionality of these pieces. Recently, considerable attention has been focused on developing methods to control the site and number of linker/drug conjugated to the antibody, with the aim of producing more homogenous ADCs. In this article, we review popular conjugation methods and highlight recent approaches including “click” conjugation and enzymatic ligation. We discuss current linker technology, contrasting the characteristics of cleavable and non-cleavable linkers, and summarize the essential properties of ADC payload, centering on chemotherapeutics. In addition, we report on the progress in characterizing to determine physicochemical properties and on advances in purifying to obtain homogenous products. Establishing a set of selection and analytical criteria will facilitate the translation of novel ADCs and ensure the production of effective biosimilars.
Blood-based profiles of DNA methylation predict the underlying distribution of cell types: a validation analysis.

The potential influence of underlying differences in relative leukocyte distributions in studies involving blood-based profiling of DNA methylation is well recognized and has prompted development of a set of statistical methods for inferring changes in the distribution of white blood cells using DNA methylation signatures. However, the extent to which this methodology can accurately predict cell-type proportions based on blood-derived DNA methylation data in a large-scale epigenome-wide association study (EWAS) has yet to be examined. We used publicly available data deposited in the Gene Expression Omnibus (GEO) database (accession number GSE37008), which consisted of both blood-derived epigenome-wide DNA methylation data assayed using the Illumina Infinium HumanMethylation27 BeadArray and complete blood cell (CBC) counts among a community cohort of 94 non-diseased individuals. Constrained projection (CP) was used to obtain predictions of the proportions of lymphocytes, monocytes and granulocytes for each...
A Combined Screening Platform for HIV Treatment Failure and Resistance

Background To develop a low cost method to screen for virologic failure of antiretroviral therapy (ART) and HIV-1 drug resistance, we performed a retrospective evaluation of a screening assay using serial dilutions of HIV-1 RNA-spiked blood plasma and samples from patients receiving >6 months of first-line ART. Methods Serial dilution testing was used to assess sensitivity of a simple PCR-based assay (targeted at ≥1,000 HIV RNA copies/mL). We created blood plasma minipools of five samples, extracted HIV RNA from the pools, PCR amplified the reverse transcriptase (RT) coding region of the HIV-1 pol gene from extracted RNA, sequenced PCR product of positive pools, and used sequences to determine drug resistance. Sensitivity, specificity, and predictive values were determined for different levels of virologic failure based on maximum viral loads of individual samples within a pool. Results Of 295 samples analyzed, 43 (15%) had virologic failure at ≥50 copies/mL (range 50–10,500 copies/mL, four at ≥1,000 copies/mL). The assay demonstrated 100% sensitivity to detect virus from these four samples, requiring only one round of PCR, and 56% and 89% sensitivity to detect samples with ≥50 and ≥500 copies/mL using two rounds. Amplified PCR products of all positive pools were successfully sequenced and 30% harbored ≥1 major resistance mutation. This method would have cost 10% of the combined costs of individual viral load and resistance testing. Conclusions We present a novel method that can screen for both virologic failure of first-line ART and drug resistance. The method is much less expensive than current methods, which may offer sustainability in resource-limited settings.
Glucosamine degradation by Escherichia coli. I. Observations with resting cells and dry-cell preparations

Abstract The metabolism of normal glucosamine and glucosamine-U-C 14 by resting cell suspensions and dried cell preparations of Escherichia coli was investigated. The results indicate that an anaerobic degradation pathway for glucosamine exists which is dependent upon an initial phosphorylation of glucosamine to give glucosamine 6-PO 4 . Glucosamine 6-PO 4 then serves as a substrate for further degradation to ammonia and a product presumably common to the Embden-Meyerhof glycolytic pathway. The inhibitory effect of glucose on glucosamine utilization was also studied. It was found that the presence of glucose decreased glucosamine utilization and glucosamine 6-PO 4 formation. The presence of glucose, however, had no effect on ammonia production from a glucosamine 6-PO 4 substrate. These results were interpreted to mean that a competition exists between glucose and glucosamine for the same hexokinase.
Differential modulation of TMJ neurons in superficial laminae of trigeminal subnucleus caudalis/upper cervical cord junction region of male and cycling female rats by morphine

Sex differences in the cellular responses to morphine were examined in an animal model of temporomandibular joint (TMJ) pain. TMJ-responsive neurons were recorded in the superficial laminae at the trigeminal subnucleus caudalis/upper cervical cord (Vc/C(2)) junction region, the initial site of synaptic integration for TMJ afferents, in male and cycling female rats under barbiturate anesthesia. Unit activity was evoked by local injection of bradykinin into the TMJ capsule at 30 min intervals and the effects of morphine sulfate (0.03-3 mg/kg, i.v.) were assessed by a cumulative dose regimen. Morphine caused a dose-related inhibition of bradykinin-evoked unit activity in males and diestrous females in a naloxone-reversible manner, while evoked unit activity in proestrous females was not reduced. The apparent sex hormone-related aspect of morphine analgesia was selective for evoked unit activity, since the spontaneous activity of TMJ units was reduced similarly in all groups, while the convergent cutaneous receptive field area of TMJ units did not change in any group. These results were consistent with the hypothesis that sex hormone status interacts with pain control systems to modify neural activity at the level of the Vc/C(2) junction region relevant for TMD pain.
Monitoring biomarkers of cellular injury and death in acute brain injury.

Molecular biomarkers have revolutionalized diagnosis and treatment of many diseases, such as troponin use in myocardial infarction. Urgent need for high-fidelity biomarkers in neurocritical care has resulted in numerous studies reporting potential candidate biomarkers. We performed an electronic literature search and systematic review of English language articles on cellular/molecular biomarkers associated with outcome and with disease-specific secondary complications in adult patients with acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), and post-cardiac arrest hypoxic ischemic encephalopathic injuries (HIE). A total of 135 articles were included. Though a wide variety of potential biomarkers have been identified, only neuron-specific enolase has been validated in large cohorts and shows 100 % specificity for poor outcome prediction in HIE patients not treated with therapeutic hypothermia. There are many promising candidate blood and CSF biomarkers in SAH, AIS, ICH, and TBI, but none yet meets criteria for routine clinical use. Current studies vary significantly in patient selection, biosample collection/processing, and biomarker measurement protocols, thereby limiting the generalizability of overall results. Future large prospective studies with standardized treatment, biosample collection, and biomarker measurement and validation protocols are necessary to identify high-fidelity biomarkers in neurocritical care.
Concepts in local flap design and classification

Facial reconstruction relies on the creativity of surgeons as well as a clear understanding in the properties of local flaps. Choosing the correct procedure begins with thorough analysis of the defect. Multiple reconstructive options often exist, which can then be narrowed and refined based on the specific qualities of the defect and the history of the patient. Careful planning ultimately leads to an excellent functional and aesthetic reconstructive outcome.
Abstract 666: Regulation of IGF-1 signaling by lysosomal cathepsins in neuroblastoma

Neuroblastoma is the most common extracranial solid tumor of childhood. Despite intensive combination therapies, the survival rate for children diagnosed with high-risk neuroblastoma remains below 40%, with surviving children suffering from severe side-effects of aggressive surgery, cytotoxic chemotherapy and radiation. We show that specific inhibition of a group of lysosomal proteases results in accumulation of autophagic vacuoles and eventual apoptosis of neuroblastoma cell lines. Cell death is not caused in breast and prostate cancer cell lines or mouse primary fibroblasts, indicating specificity of the apoptotic response in neuroblastoma. In this study we have examined mechanisms by which inhibition of these proteases can lead to the specific death of these tumors. IGF-1 signaling is essential for cellular proliferation, survival, and apoptotic resistance. We found that in neuroblastoma cells IGF-1 signaling is impaired by inhibition of cathepsins B and L. Western blotting shows that lower molecular weight fragments of the IGF-1 receptor beta subunit accumulate in inhibitor-treated cells, indicating that lysosomal proteases are essential for the complete the degradation of the IGF-1 receptor. Phosphorylation and activation of full-length IGF-1 receptor was not modified by inhibitor treatment, but phosphorylation and activation of MAPK and Akt (downstream effectors of IGF-1 receptor signaling) was greatly diminished. Fractionation of cellular lysates showed that the IGF-1R β fragments accumulate in compartments that contain a cleaved form of LC-3, a marker of autophagic vacuoles. Intermediates of the IGF-1 signaling cascade were also sequestered within these compartments, and significantly depleted in the cytoplasm. We conclude that inhibition of lysosomal proteases results in sequestration of critical components of the cell signaling transduction pathway, causing cell death by uncoupling of cell surface and endosomal signaling from intracellular effector signals. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 666.
Hydrogen Diffusion and Thermal Equilibrium of Electronic States in a-Si:H

This paper reviews the recent evidence for thermal equilibrium effects in the electronic behavior of hydrogenated amorphous silicon, and relates the thermally induced changes to the motion of bonded hydrogen. The electronic properties are studied through measurements of d.c conductivity and-.weep out, and the role of hydrogen is explored through its diffusion. The magnitude and doping dependence of the diffusion coefficient DH matches the data on the equilibration of the electronic states. Furthermore both the diffusibn and the relaxation can be described by the same dispersive time dependence. It is argued that the diffusion of hydrogen is the rate limiting step in the the equilibration mechanisms and determines the kinetics.
Properties of metal semiconductor contacts—I voltage-current characteristics of contacts on intrinsic semiconductors

In the general case (two carriers, arbitrary lifetime, arbitrary dielectric relaxation time), the transport equations relating to barrier characteristics have to be solved by numerical methods. The single-carrier case is already (abundantly) familiar, but the two-carrier case can also be solved explicitly. However, the solution is at all simple only for contacts on high lifetime intrinsic material. Such a solution is here obtained by conventional analytic methods, based on the diffusion theory and reasonable approximations, and is compared with computed results obtained on the complete (unapproximated) system. Analysis and computation lead to new and hitherto unrecognized dependence of the current on the applied voltage across the barrier in accordance with exp[2qVa/kT], instead of the more familiar exp[qVa/kT]. The computational aspects as such receive detailed attention in Part II. The conclusions have important implications for the interpretation of non-ideality factors. The intrinsic case here treated reflects general modes of behavior; more specific results for extrinsic systems will be presented in Part III.
The significance and treatment of blood pressure elevation associated with toxemia of pregnancy and acute nephritis.

Abstract The fact that the characteristic renal biopsy picture of toxemia of pregnancy is that of membranous glomerulonephritis adequately explains the similarity of toxemia to glomerulonephritis. Although the exact pathogenesis of both these diseases is not clear, the signs and symptoms are readily explained by abnormal sodium retention and generalized vasoconstriction. The relationship between these abnormalities remains unknown but clinical observation attests to the fact that in toxemia of pregnancy, sodium retention usually precedes generalized vasoconstriction and its prompt therapy prevents the development of generalized vasoconstriction. In toxemia, therefore, prompt and continued therapy of sodium retention with the thiazides constitutes the most important therapy. In the hypertensive patient with glomerulonephritis signs of both sodium retention and generalized vasoconstriction are generally present when the patient is first examined. In these patients both sodium diuretic agents and vasodilating agents are indicated.
Effect of beta-adrenergic receptor blockade on responses to acute hypoxemia in lambs.

ABSTRACT: We studied the effects of β-adrenergic receptor blockade on general circulatory and metabolic responses to moderate (FIO2 = 0.09) acute hypoxemia in newborn (protocol 1) and 3-wk-old (protocol 2) lambs, and on regional blood flow distribution in newborn lambs (protocol 1). Via a left thoracotomy we placed an electromagnetic flow transducer around the ascending aorta and inserted various vascular catheters. After 2 days of recovery, the lambs were studied. In protocol 1, we measured cardiovascular variables and regional blood flow distribution during control conditions, after 45 min of acute hypoxemia, and after 0.5 mg/kg of propranolol during acute hypoxemia. In protocol 2, we measured cardiovascular variables during control conditions and after 45 min of acute hypoxemia with and without propranolol pretreatment. In both groups, propranolol limited the increase in cardiac output and heart rate caused by hypoxemia, and thus decreased oxygen delivery. However, propranolol also decreased oxygen consumption so that pulmonary arterial pO2 was either higher (protocol 1) or the same (protocol 2) as during acute hypoxemia alone. Neither metabolic acidosis nor hypothermia ensued. In protocol 1, propranolol decreased renal, carcass, and most importantly, myocardial blood flows. However, myocardial O2 consumption also fell, coronary sinus pO2 increased, and blood was redistributed toward the subendocardium, suggesting that myocardial perfusion improved. Thus, β-adrenergic receptor blockade during acute moderate hypoxemia may have a beneficial effect by reducing total body and myocardial oxygen demand in excess of the reduction in oxygen delivery.
Gene expression based evidence of innate immune response activation in the epithelium with oral lichen planus.

Abstract Objective Oral lichen planus (OLP) is a disease of the oral mucosa of unknown cause producing lesions with an intense band-like inflammatory infiltrate of T cells to the subepithelium and keratinocyte cell death. We performed gene expression analysis of the oral epithelium of lesions in subjects with OLP and its sister disease, oral lichenoid reaction (OLR), in order to better understand the role of the keratinocytes in these diseases. Design Fourteen patients with OLP or OLR were included in the study, along with a control group of 23 subjects with a variety of oral diseases and a normal group of 17 subjects with no clinically visible mucosal abnormalities. Various proteins have been associated with OLP, based on detection of secreted proteins or changes in RNA levels in tissue samples consisting of epithelium, stroma, and immune cells. The mRNA level of twelve of these genes expressed in the epithelium was tested in the three groups. Results Four genes showed increased expression in the epithelium of OLP patients: CD14, CXCL1, IL8, and TLR1, and at least two of these proteins, TLR1 and CXCL1, were expressed at substantial levels in oral keratinocytes. Conclusions Because of the large accumulation of T cells in lesions of OLP it has long been thought to be an adaptive immunity malfunction. We provide evidence that there is increased expression of innate immune genes in the epithelium with this illness, suggesting a role for this process in the disease and a possible target for treatment.
Structure-based design of selective inhibitors of dihydrofolate reductase: synthesis and antiparasitic activity of 2, 4-diaminopteridine analogues with a bridged diarylamine side chain.

As part of a larger search for potent as well as selective inhibitors of dihydrofolate reductase (DHFR) enzymes from opportunistic pathogens found in patients with AIDS and other immune disorders, N-[(2,4-diaminopteridin-6-yl)methyl]dibenz[b,f]azepine (4a) and the corresponding dihydrodibenz[b,f]azepine, dihydroacridine, phenoxazine, phenothiazine, carbazole, and diphenylamine analogues were synthesized from 2,4-diamino-6-(bromomethyl)pteridine in 50−75% yield by reaction with the sodium salts of the amines in dry tetrahydrofuran at room temperature. The products were tested for the ability to inhibit DHFR from Pneumocystis carinii (pcDHFR), Toxoplasma gondii (tgDHFR), Mycobacterium avium (maDHFR), and rat liver (rlDHFR). The member of the series with the best combination of potency and species selectivity was 4a, with IC50 values against the four enzymes of 0.21, 0.043, 0.012, and 4.4 μM, respectively. The dihydroacridine, phenothiazine, and carbazole analogues were also potent, but nonselective. Of the ...