cssi/SciSciGPT-SciSciNet huggingface dataset:
Therapeutic Potential of Tachykinin Receptor Antagonists in Depression and Anxiety Disorders

Neuropeptides, including the tachykinins substance P, neurokinin A and neurokinin B, are potentially important new targets for the development of psychotropic drugs. NK1, NK2 and NK3 tachykinin receptor antagonists are currently undergoing clinical trials to investigate their therapeutic applications in central nervous system (CNS) disorders. Substance P (NK1) receptor antagonists (NK1RAs) have been clinically valid ated as a novel approach to treat major depression. Confirmation of the antidepressant efficacy of NK1RAs has been obtained with three separate compounds in double-blind, placebo-controlled clinical trials. NK1RAs are active in a range of preclinical assays that detect clinically used antidepressant and anxiolytic drugs, but they have a profile of activity that is distinct from established drugs. There is preliminary evidence that substance P function may be altered in depressed patients, suggesting a possible link between substance P and depressive pathophysiology. Preclinical studies indicate that the psychotherapeutic effects of NK1RAs may be mediated by direct blockade of NK1 receptors in the amygdala and its associated output projections, through stimulation of hippocampal neurogenesis, and also via interactions with monoamines. Clinical assessment of NK2 and NK3 receptor antagonists in psychiatric disorders is currently in progress.
Exploiting Intra-Conversation Variability for Speaker Diarization

In this paper, we propose a new approach to speaker diarization based on the Total Variability approach to speaker verification. Drawing on previous work done in applying factor analysis priors to the diarization problem, we arrive at a simplified approach that exploits intra-conversation variability in the Total Variability space through the use of Principal Component Analysis (PCA). Using our proposed methods, we demonstrate the ability to achieve state-of-the-art performance (0.9% DER) in the diarization of summed-channel telephone data from the NIST 2008 SRE. Index Terms: speaker diarization, factor analysis, Total Variability, principal component analysis
In Situ Characterization of thin film Growth by Ftir Irras

In-situ analysis of low temperature Plasma Enhanced Chemical Vapor Deposition (PECVD) SiO2 films deposited on HgCdTe, Silicon, and Aluminum substrates was performed by double modulation Fourier Transform Infrared Reflection Absorption spectroscopy (FT-IRRAS). The sensitivity and selectivity of this technique are sufficient for an in-situ assessment of the film quality and reaction conditions at any stage of film growth. An oblique angle of incidence of ca. 557deg; was chosen to yield maximum sensitivity for the 1260 cm−1 LO mode of SiO2 on Si. The peak frequency and shape of the LO mode absorption band varied with the quality of the SiO2 films. This diagnostic technique can be applied readily to in-situ analysis of dielectric thin films formed under a variety of reaction conditions as long as the gaseous ambient is partially transmissive to the IR radiation.
Study on clinical effect and recurrence of micro operation treatment of parasellar meningiomas

Objective To study the microscopic operation treatment of sellar meningioma clinical effect and influence factors of recurrence. Method Retrospective analysis of our hospital from November 2008 to November 2012, 268 patients with parasagittal meningiomas treated in our department in patients with clinical data, all patients were treated with microsurgical operation treatment, observe and analyze the extent of resection, postoperative mortality of operation and clinical complications, quality of life of the patients with tumor recurrence, etc. Result After different range of resection, patients KPS contrast show significant difference(P 0.05). The higher the WHO classification, the postoperative recurrence rate was higher, Cavernous sinus violation less postoperative recurrence in patients with a significant rise in patients with cavernous sinus, with significant difference(P0.05), between the variant and atypical meningioma patients postoperative recurrence rate is significantly increased in patients with benign meningiomas, has the extremely significant difference(P0.01). Conclusion The preferred treatment for patients with parasellar meningioma operation excision, cavernous sinus invasion in patients should be closely observed, greater risk of anaplastic and atypical meningioma recurrence, should be routine in postoperative radiotherapy. Micro operation treatment of parasellar meningioma long-term efficacy, should be popularized.
Shared education in Northern Ireland: school collaboration in divided societies

AbstractDuring the years of political violence in Northern Ireland many looked to schools to contribute to reconciliation. A variety of interventions were attempted throughout those years, but there was little evidence that any had produced systemic change. The peace process provided an opportunity for renewed efforts. This paper outlines the experience of a series of projects on 'shared education', or the establishment of collaborative networks of Protestant, Catholic and integrated schools in which teachers and pupils moved between schools to take classes and share experiences. The paper outlines the genesis of the idea and the research which helped inform the shape of the shared education project. The paper also outlines the corpus of research which has examined various aspects of shared education practice and lays out the emergent model which is helping to inform current government practice in Northern Ireland, and is being adopted in other jurisdictions. The paper concludes by looking at the prospect...
[Study of three ciguatera fish poisoning cases in Xiamen city, in 2005].

Objective To find out the reason of three eiguatem fish poisoning cases in Xiaman in 2005 and identify the fish species.Methods The grouper implicated in food poisoning and seven other coral reef fishes collected from market were tested by mice bioassay and ciguatoxin-test kit.The mtDNA was extracted from toxic grouper meat,and Cty b gene segment was amplified and the PCR products were sequenced.The sequences were compared with those in the GenBank.Results The result turned out to be positive by the ciguatoxin-test kit,while the toxicity of the toxic grouper implicated in food poisoning was 0.11 mouse unit(MU)/g by mice bioassay.A 475 bp segments of Cty b gene was amplified by PCR and the sequence was 99% homologous with Epinephelus fuscoguttatus(GenBank:AY950695).No ciguatoxin in six grouper species collected from market was detected.Conclusion All three food poisoning cases were caused by consumption of ciguatoxin-carrying groupers. Key words: Toxins,biological; Poisoning; Fishes; Ciguatoxins
On detecting environment sensitivity using slicing

Abstract Modern malware often evades debuggers, virtual machines, and emulators. It is interesting if one can observe their behavior difference using controlled environments. This paper formalizes the notion of environment sensitivity, and proposes two alternative semantics: one based on program trace and the other based on code coverage. Then it tackles the following question: can one minimize an environment sensitive program? The work presents progressive executable slice, a subprogram generated from a partial control but full data dependency closure of a program under study. It shows that a progressive slice can retain trace based environment sensitivity but not the code coverage sensitivity, for which, a special condition is needed for restraining the slice. The saturated trace set of a program is used as a cost indicator for observing its behavior difference. The paper shows that a progressive slice does not necessarily have a lower observation cost than its container program. To address it, a consistency condition is proposed. The paper introduces a reference algorithm for generating progressive slices, and discusses its approximation in practice.
Exploring Pathways for Building Trust in Vaccination and Strengthening Health System Resilience

Trust is critical to generate and maintain demand for vaccines in low and middle income countries. However, there is little documentation on how health system insufficiencies affect trust in vaccination and the process of re-building trust once it has been compromised. We reflect on how disruptions to immunizations systems can affect trust in vaccination and can compromise vaccine utilization. We then explore key pathways for overcoming system vulnerabilities in order to restore trust, to strengthen the resilience of health systems and communities, and to promote vaccine utilization. Utilizing secondary data and a review of the literature, we developed a causal loop diagram (CLD) to map the determinants of building trust in immunizations. Using the CLD, we devised three scenarios to illustrate common vulnerabilities that compromise trust and pathways to strengthen trust and utilization of vaccines, specifically looking at weak health systems, harmful communication channels, and role of social capital. Spill-over effects, interactions and other dynamics in the CLD were then examined to assess leverage points to counter these vulnerabilities. Trust in vaccination arises from the interactions among experiences with the health system, the various forms of communication and social capital – both external and internal to communities. When experiencing system-wide shocks such as the case in Ebola-affected countries, distrust is reinforced by feedback between the health and immunization systems where distrust often lingers even after systems are restored and spills over beyond vaccination in the broader health system. Vaccine myths or anti-vaccine movements reinforce distrust. Social capital – the collective value of social networks of community members – plays a central role in increasing levels of trust. Trust is important, yet underexplored, in the context of vaccine utilization. Using a CLD to illustrate various scenarios helped to explore how common health and vaccine vulnerabilities can reinforce and spill over distrust through vicious, reinforcing feedback. Restoring trust requires a careful balance between eliminating vulnerabilities and strengthening social capital and interactions among communication channels.
Analysis of Mo Sidewall Ohmic Contacts to InGaAs Fins

We present a novel test structure for the study of sidewall ohmic contacts to III–V fins for FinFETs. We apply it to the characterization of the impact of digital etch (DE), used to trim the fin width, and thermal annealing on the contact resistivity of Mo/ $\text{n}^{+}$ -InGaAs fin sidewall contacts. To obtain sidewall contacts, we leave in place the etch mask that is used to define the fins in a reactive ion etching process and deposit conformal Mo around them. We present a model that describes well the electrical characteristics of the test structure. In our results, we find that the specific acid that is used for DE or the number of DE cycles that are performed have a minor impact on contact resistivity. Thermal annealing is found to significantly improve the sidewall contact resistivity, with the best value of $3.7~ \pm ~0.2~ {\Omega } \cdot {\mu } \text{m}^{{2}}$ obtained after annealing at 400 °C. This is about three times higher than the reported contact resistivity for this contact technology with the contact wrapping around the top and the sidewall surfaces of fins, about $1.3~ {\Omega } \cdot {\mu }\text{m}^{{2}}$ . Also, we find that the width of the non-conductive region under the sidewall surface of Mo contact, which we term “deadzone,” can be significantly mitigated by thermal annealing. Our work highlights the importance of understanding sidewall ohmic contact formation for future high-performance InGaAs FinFETs.
The Influence of Emotional State on Learning From Reward and Punishment in Borderline Personality Disorder.

Despite preliminary evidence that individuals with borderline personality disorder (BPD) demonstrate deficits in learning from corrective feedback, no studies have examined the influence of emotional state on these learning deficits in BPD. This laboratory study examined the influence of negative emotions on learning among participants with BPD (n = 17), compared with clinical (past-year mood/anxiety disorder; n = 20) and healthy (n = 23) controls. Participants completed a reinforcement learning task before and after a negative emotion induction. The learning task involved presenting pairs of stimuli with probabilistic feedback in the training phase, and subsequently assessing accuracy for choosing previously rewarded stimuli or avoiding previously punished stimuli. ANOVAs and ANCOVAs revealed no significant between-group differences in overall learning accuracy. However, there was an effect of group in the ANCOVA for postemotion induction high-conflict punishment learning accuracy, with the BPD group sho...
Polyphenolic Polymersomes of Temperature-Sensitive Poly(N-vinylcaprolactam)-block-Poly(N-vinylpyrrolidone) for Anticancer Therapy.

We report a versatile synthesis for polyphenolic polymersomes of controlled submicron (<500 nm) size for intracellular delivery of high and low molecular weight compounds. The nanoparticles are synthesized by stabilizing the vesicular morphology of thermally responsive poly(N-vinylcaprolactam)n-b-poly(N-vinylpyrrolidone)m (PVCLn–PVPONm) diblock copolymers with tannic acid (TA), a hydrolyzable polyphenol, via hydrogen bonding at a temperature above the copolymer’s lower critical solution temperature (LCST). The PVCL179–PVPONm diblock copolymers are produced by controlled reversible addition–fragmentation chain transfer (RAFT) polymerization of PVPON using PVCL as a macro-chain transfer agent. The size of the TA-locked (PVCL179–PVPONm) polymersomes at room temperature and upon temperature variations are controlled by the PVPON chain length and TA:PVPON molar unit ratio. The particle diameter decreases from 1000 to 950, 770, and 250 nm with increasing PVPON chain length (m = 107, 166, 205, 234), and it furth...
Mental Health Insurance Parity and Provider Wages.

BACKGROUND Policymakers frequently mandate that employers or insurers provide insurance benefits deemed to be critical to individuals' well-being. However, in the presence of private market imperfections, mandates that increase demand for a service can lead to price increases for that service, without necessarily affecting the quantity being supplied. We test this idea empirically by looking at mental health parity mandates. OBJECTIVE This study evaluated whether implementation of parity laws was associated with changes in mental health provider wages. METHOD Quasi-experimental analysis of average wages by state and year for six mental health care-related occupations were considered: Clinical, Counseling, and School Psychologists; Substance Abuse and Behavioral Disorder Counselors; Marriage and Family Therapists; Mental Health Counselors; Mental Health and Substance Abuse Social Workers; and Psychiatrists. Data from 1999-2013 were used to estimate the association between the implementation of state mental health parity laws and the Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act and average mental health provider wages. RESULTS Mental health parity laws were associated with a significant increase in mental health care provider wages controlling for changes in mental health provider wages in states not exposed to parity (3.5 percent [95% CI: 0.3%, 6.6%]; p<.05). DISCUSSION Mental health parity laws were associated with statistically significant but modest increases in mental health provider wages. IMPLICATIONS Health insurance benefit expansions may lead to increased prices for health services when the private market that supplies the service is imperfect or constrained. In the context of mental health parity, this work suggests that part of the value of expanding insurance benefits for mental health coverage was captured by providers. Given historically low wage levels of mental health providers, this increase may be a first step in bringing mental health provider wages in line with parallel health professions, potentially reducing turnover rates and improving treatment quality.
Biocidal effectiveness of combustion products of iodine-bearing reactive materials against aerosolized bacterial spores

Abstract Mechanochemically prepared metal-based iodine bearing reactive materials (RMs), generate I2 gas among other combustion products, and are therefore of interest as biocidal additives in agent defeat applications. In order to facilitate future use of these RMs, a phenomenological model is proposed that describes biocidal effectiveness of ternary Al·B·I2 composites against aerosolized spores of Bacillus thuringiensis (Btk), a Bacillus anthracis surrogate. The model is based on experiments, in which aerosolized spores passed through an enclosed flow system, where on a sub-second time scale they were exposed to elevated temperatures and combustion products of different RM powders injected in an air-acetylene flame. Temperature distribution, and flow conditions in the exposure chamber were varied to achieve different temperature, iodine concentration profiles, and exposure times. The exposure effect was quantified experimentally via an inactivation factor IF, defined as the inverse fraction of microorganisms surviving the exposure. The process observed in the experiments was described using computational fluid dynamics (CFD) modeling, treating the bacterial spores as 1-µm unit-density particles injected in the airflow, and assuming continuous iodine release during RM particle combustion. To quantify the biocidal effect for each spore, an integral exposure function was introduced consisting of two Arrhenius terms corresponding to pure thermal and iodine-related inactivation. The corresponding activation energies were found as E1 = 5 kJ/mol, and E2 = 10 kJ/mol, respectively. The rate constant for the iodine-concentration dependent term was found as 32.3 m3/mol multiplied by the iodine concentration in mol/m3. A critical total exposure threshold was identified. Since the model proposed here depends only on thermal exposure and on iodine, it may be valid for a wider range of iodine bearing RMs.
Basic Ideas in Probability

We will perform experiments—which could be pretty much anything, from flipping a coin, to eating too much saturated fat, to smoking, to crossing the road without looking—and reason about the outcomes (mostly bad for the examples I gave). But these outcomes are uncertain, and we need to weigh those uncertainties against one another. If I flip a coin, I could get heads or tails, and there’s no reason to expect to see one more often than the other. If I eat too much saturated fat or smoke, I will very likely have problems, though I might not. If I cross the road without looking, I may be squashed by a truck or I may not. Our methods need also to account for information. If I look before I cross the road, I am much less likely to be squashed. Probability is the machinery we use to describe and account for the fact that some outcomes are more frequent than others.
Health literacy and knowledge of female reproduction in undergraduate students

College students make many important decisions related to sexual health, but little is known about their reproductive health knowledge. The purpose of the study was to examine health literacy and k...
Feasibility of Ideal Cardiovascular Health Evaluation in a Pediatric Clinic Setting

The feasibility of "point-of-care" screening for ideal cardiovascular health was explored in a pediatric specialty clinic setting. Children and adolescents aged 9-18 years (n=91) with treated and stabilized diseases were recruited at a pediatric endocrinology clinic. A table-top device was used to assay fingerstick samples for non-HDL cholesterol (non-HDL-C), which was used to divide participants into two groups based on the non-HDL-C threshold for comparison of the remaining metrics between groups. A significant number of children had low scores, and score frequency distribution was similar to larger retrospective studies, with few participants achieving none or all of the health metrics. Healthy diet was the metric least often achieved. Those with a non-HDL-C above the ideal threshold of 3.1 mmol/L (120 mg/dl) had a higher BMI percentile (p<0.01) and diastolic blood pressure percentile (p<0.05). We conclude that pediatric risk factor screening and scoring can be performed in a specialty clinic with meaningful cardiovascular health scores for patients and providers. Association of abnormal "point-of care" non-HDL-C levels with elevated BMI and blood pressure supports evidence for risk factor clustering and use of the ideal health construct in pediatric clinic settings.
A Gap in the Literature: The Influence of the Design, Operations, and Marketing of Student Aid Programs on College-Going Plans and Behaviors

This article describes what is known from prior research about the impact of student financial aid program design, operations, and marketing on the formation of family (including parents’ and children’s) college-going aspirations, expectations, and plans, and the resulting college-going behaviors of potential students. The review focuses on the experiences of lower-income, minority, and potential first-generation college students. Disciplines Bilingual, Multilingual, and Multicultural Education | Disability and Equity in Education | Education | Educational Sociology | Education Economics | Family, Life Course, and Society | Race and Ethnicity This journal article is available at ScholarlyCommons: http://repository.upenn.edu/gse_pubs/285 7 NASFAA JOURNAL OF STUDENT FINANCIAL AID A Gap in the Literature: The Influence of the Design, Operations, and Marketing of Student Aid Programs on College-Going
Decidability of contextual reasoning

Contexts were first suggested in McCarthy’s Turing Award Paper, (McCarthy 1987), as a possible solution to the problem of generality in AI. McCarthy’s concern with the existing AI systems has been that they can reason only about some particular, predetermined task. When faced with slightly different circumstances they need to be completely rewritten. In other words, AI systems lack generality. Cyc (Guha & Lenat 1990), a large common-sense knowledge-base currently being developed at MCC, is one example of where contexts have already been put to use in attempt to solve the problem of generality. Because of the complexity of the problem of generality, it has been speculated that any reasoning system which would be able to solve this problem would itself be computationally unacceptable. The purpose of this paper is to show that propositional contextual reasoning is decidable.
Micromechanics effects in creep metal-matrix composites

When placed under tensile loading, metals tend to creep, i.e., to elongate slowly over times of order hours to days. The creep rate is proportional to σ n where σ is the applied stress andn istypically in the range 2< n < 15. Ifnon-creeping, reinforcing particles are added to the metal, the creep rate of the composite is substantially reduced. On December 2, 1994 L. Craig Davis from Ford Motor Company described his recent work with J.E. Allison [1] in which the creep of metal-matrix composites was analyzed by finite element techniques. He posed, as an open problem, establishing by mathematical analysis the principal results of his calculations.
Cf-252 Neutron Therapy and Neutron Capture Therapy

The potential of fast fission neutrons in the treatment of malignant tumors has been studied by Koester et al 1. These studies have been folt,owed by clinical trials of superficial tumor treatment at the Munich research reactor2 and by further studies of possible use of neutron capture reaction (NCT). For clinical trials of fast fission neutron therapy or NCT, nuclear reactors are the best source of neutrons. However, for routine therapy nuclear reactors are too expensive and hazardous to be based in a hospital or in an urban area.
Putting language into language modeling.

In this paper we describe the statistical Structured Language Model (SLM) that uses grammatical analysis of the hypothesized sentence segment (prefix) to predict the next word. We first describe the operation of a basic, completely lexicalized SLM that builds up partial parses as it proceeds left to right. We then develop a chart parsing algorithm and with its help a method to compute the prediction probabilities P (wi+1jWi): We suggest useful computational shortcuts followed by a method of training SLM parameters from text data. Finally, we introduce more detailed parametrization that involves non-terminal labeling and considerably improves smoothing of SLM statistical parameters. We conclude by presenting certain recognition and perplexity results achieved on standard corpora.
Single Particle Analysis at High Resolution

Electron cryomicroscopy (cryo-EM) and single particle analysis is emerging as a powerful technique for determining the 3D structure of large biomolecules and biomolecular assemblies in close to their native solution environment. Over the last decade, this technology has improved, first to sub-nanometer resolution, and more recently beyond 0.5 nm resolution. Achieving sub-nanometer resolution is now readily approachable on mid-range microscopes with straightforward data processing, so long as the target specimen meets some basic requirements. Achieving resolutions beyond 0.5 nm currently requires a high-end microscope and careful data acquisition and processing, with much more stringent specimen requirements. This chapter will review and discuss the methodologies for determining high-resolution cryo-EM structures of nonvirus particles to sub-nanometer resolution and beyond, with a particular focus on the reconstruction strategy implemented in the EMAN software suite.
Abstract 2537: Regulation of LMO2 oncogene expression in high-risk B-cell acute lymphoblastic leukemia

LIM domain only protein 2 (LMO2) is an oncogene that is overexpressed in a subset of B-cell acute lymphoblastic leukemia (B-ALL). The mechanisms that regulate LMO2 expression in B-ALL are still unknown. Here, we show that transcription of LMO2 in B-ALL is regulated by Ikaros, a tumor suppressor protein, which is encoded by the IKZF1 gene, and whose deletion is associated with development of high-risk B-ALL. The use of global chromatin immunoprecipitation coupled with the next-generation sequencing (ChIP-seq) studies in primary human B-ALL cells and in cell lines revealed a strong Ikaros occupancy at the promoter of the LMO2 gene. Ikaros binding to the LMO2 promoter was confirmed by quantitative chromatin immunoprecipitation (qChIP). We tested the role of Ikaros in regulating LMO2 transcription in B-ALL using gain-of-function and loss-of-function experiments. A luciferase reporter assay with the LMO2 promoter showed that Ikaros directly represses LMO2 transcription. Overexpression of Ikaros in B-ALL via retroviral transduction was associated with strongly reduced expression of LMO2. Furthermore, Ikaros knock-down with shRNA, resulted in increased transcription of LMO2 in B-ALL cells. These results suggest that Ikaros represses transcription of LMO2 in B-ALL. Since Ikaros9 function in B-ALL is negatively regulated by pro-oncogenic Casein Kinase II (CK2), we tested whether CK2 inhibition affects Ikaros-mediated repression of LMO2. Both molecular inhibition with shRNA, and pharmacological inhibition of CK2 with a specific CK2 inhibitor, CX-4945, resulted in reduced expression of LMO2. Inhibition of CK2 was also associated with increased Ikaros occupancy at the LMO2 promoter. In high-risk B-ALL that have deletion of a single copy of the IKZF1 gene, Ikaros does not bind to the LMO2 promoter. Treatment of primary B-ALL cells that have IKZF1 haploinsufficiency restores Ikaros binding to the LMO2 promoter and results in reduced LMO2 expression. In conclusion, our data demonstrate that Ikaros and CK2 regulate transcription and overall expression of the LMO2 oncogene in B-ALL. Our results identify a novel mechanism of therapeutic action of CK2 inhibitors in high-risk B-ALL—repression of LMO2 expression via restoration of Ikaros9 tumor suppressor function. Citation Format: Yali Ding, Jonathon L. Payne, Shriya Kane, Elanora Dovat, Mario Soliman, Chunhua Song, Sinisa Dovat. Regulation of LMO2 oncogene expression in high-risk B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2537.
Proanthocyanidin subunit composition determined by functionally diverged dioxygenases

Proanthocyanidins (PAs) are primarily composed of the flavan-3-ol subunits (-)-epicatechin and/or (+)-catechin, but the basis for their different starter and extension unit compositions remains unclear. Genetic and biochemical analyses show that, in the model legume Medicago truncatula, two 2-oxoglutarate-dependent dioxygenases, anthocyanidin synthase (ANS) and its homologue leucoanthocyanidin dioxygenase (LDOX), are involved in parallel pathways to generate, respectively, the (-)-epicatechin extension and starter units of PAs, with (+) catechin being an intermediate in the formation of the (-)-epicatechin starter unit. The presence/absence of the LDOX pathway accounts for natural differences in PA compositions across species, and engineering loss of function of ANS or LDOX provides a means to obtain PAs with different compositions and degrees of polymerization for use in food and feed. Proanthocyanidins (PAs) are a class of plant natural products that are involved in plant defence and are also beneficial to human health. Now a new mechanism is discovered to elucidate the origin of PA units and explain the diversity of PA production in different plant species and tissues.
Improved mutant function prediction via PACT: Protein Analysis and Classifier Toolkit

MOTIVATION Deep mutational scanning experiments have enabled the measurement of the sequence-function relationship for thousands of mutations in a single experiment. The Protein Analysis and Classifier Toolkit (PACT) is a Python software package that marries the fitness metric of a given mutation within these experiments to sequence and structural features enabling downstream analyses. PACT enables the easy development of user sharable protocols for custom deep mutational scanning experiments as all code is modular and reusable between protocols. Protocols for mutational libraries with single or multiple mutations are included. To exemplify its utility, PACT assessed two deep mutational scanning datasets that measured the tradeoff of enzyme activity and enzyme stability. RESULTS PACT efficiently evaluated classifiers that predict protein mutant function tested on deep mutational scanning screens. We found that the classifiers with the lowest false positive and highest true positive rate assesses sequence homology, contact number and if mutation involves proline. AVAILABILITY AND IMPLEMENTATION PACT and the processed datasets are distributed freely under the terms of the GPL-3 license. The source code is available at GitHub (https://github.com/JKlesmith/PACT). SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
How Does Public External Debt Affect the Cost of Corporate Borrowing? Evidence from Syndicated Loans in Emerging Markets

We estimate the effect of sovereign external debt on corporate external borrowing costs using data on the yield spreads on syndicated loans issued by foreign banks in 38 emerging markets during the period 1990-2006. Our results show a significant and sizable positive effect of public external debt on loan spreads, suggesting that a higher level of sovereign external debt increases the perceived riskiness of lending to emerging market firms. We also find that the effect of public external debt on loan spreads is stronger in economies with weak creditor protection. This finding is consistent with creditors seeking higher premium against the possibility of a debt crisis in countries where the creditor protection is weak. Overall, our findings underscore the costs of fiscal profligacy for the corporate sector even when debt is issued in foreign markets.
Ankle Dorsiflexion Strength Monitoring by Combining Sonomyography and Electromyography

Ankle dorsiflexion produced by Tibialis Anterior (TA) muscle contraction plays a significant role during human walking and standing balance. The weakened function or dysfunction of the TA muscle often impedes activities of daily living (ADL). Powered ankle exoskeleton is a prevalent technique to treat this pathology, and its intelligent and effective behaviors depend on human intention detection. A TA muscle contraction strength monitor is proposed to evaluate the weakness of the ankle dorsiflexion. The new method combines surface electromyography (sEMG) signals and sonomyography signals to estimate ankle torque during a voluntary isometric ankle dorsiflexion. Changes in the pennation angle (PA) are derived from the sonomyography signals. The results demonstrate strong correlations among the sonomyography-derived PA, the sEMG signal, and the measured TA muscle contraction force. Especially, the TA muscle strength monitor approximates the TA muscle strength measurement via a weighted summation of the sEMG signal and the PA signal. The new method shows an improved linear correlation with the muscle strength, compared to the correlations between the muscle strength and sole sEMG signal or sole PA signal, where the R-squared values are improved by 4.21 % and 1.99 %, respectively.
Validation of a De‐Immunization Strategy for Monoclonal Antibodies Using Cynomolgus Macaque as a Surrogate for Human

The immunogenicity of biotherapeutics presents a major challenge during the clinical development of new protein drugs including monoclonal antibodies. To address this, multiple humanization and de-immunization techniques that employ in silico algorithms and in vitro test systems have been proposed and implemented. However, the success of these approaches has been variable and to date, the ability of these techniques to predict immunogenicity has not been systematically tested in humans or other primates. This study tested whether antibody humanization and de-immunization strategies reduce the risk of anti-drug antibody (ADA) development using cynomolgus macaque as a surrogate for human. First human-cyno chimeric antibodies were constructed by grafting the variable domains of the adalimumab and golimumab monoclonal antibodies onto cynomolgus macaque IgG1 and Igκ constant domains followed by framework germlining to cyno to reduce the xenogenic content. Next, B and T cell epitopes and aggregation-prone regions were identified using common in silico methods to select domains with an ADA risk for additional modification. The resultant engineered antibodies had a comparable affinity for TNFα, demonstrated similar biophysical properties, and exhibited significantly reduced ADA levels in cynomolgus macaque compared with the parental antibodies, with a corresponding improvement in the pharmacokinetic profile. Notably, plasma concentrations of the engineered antibodies were quantifiable through 504 hours (chimeric) and 840 hours (germlined/de-immunized), compared with only 336 hours (adalimumab) or 336-672 hours (golimumab). The results point to the significant value in the investment in these engineering strategies as an important guide for monoclonal antibody optimization that can contribute to improved clinical outcomes.
Deep-learning-enabled generative models for plasmonic metastructures (Conference Presentation)

The need for light manipulation on the nanoscale has prompted the recent advent and prosperity of plasmonic metastructures. To fully unlock the potential of such engineered optical media, plasmonic structures are exploited with progressively greater complexity, including those with arbitrarily complicated topology, spatially variant building blocks, and multi-layered configurations. The astronomical degrees of freedom associated with such structures have obstructed effective design and implementation schemes based on the conventional wisdom. We have developed a series of deep-learning enabled generative frameworks for the inverse design of plasmonic structures in response to on-demand optical properties, with extended case studies and experimental demonstrations.
Consumption of a Branched-Chain Amino Acid (BCAA) during Days 2–10 of Pregnancy Causes Abnormal Fetal and Placental Growth: Implications for BCAA Supplementation in Humans

A relatively large branched-chain amino acid (BCAA) supplement, consumed for more than 10 days, appears to be especially effective at alleviating muscle damage and soreness during intense human training. However, perturbations in amino acid and protein consumption could have unwanted transgenerational effects on male and female reproduction. This paper hypothesizes that isoleucine consumption by female mice from days 2 to 10 of pregnancy will alter fetal and placental growth later in gestation. Mice that had received 118 mM isoleucine in their drinking water delivered pups on day 19 of pregnancy that were 9% larger than normal, whereas the reverse was true for pups born on day 20. Moreover, the inverse correlation between birth weight and litter size was lost in mice that previously consumed excess isoleucine. Similarly, the normal correlations between fetal and placental weights were lost by day 18 of pregnancy in mice that had consumed excess isoleucine. Mice that consumed excess isoleucine had placentas smaller than, and fetuses larger than normal on day 18 of pregnancy, but the reverse was true on day 15. Other unintended and unexpected effects of BCAA consumption should be studied more thoroughly due to the increasing use of BCAAs to alleviate muscle damage and soreness in athletes.
Development of a Questionnaire to Assess Patient Priorities in Hip Fracture Care.

Background:Patient reported outcome measures (PROMs) are becoming well recognized as an important component of health care outcomes and determinants of value in patient-centered care. Yet, there is...
Subjective well-being among male veterans in later life: the enduring effects of early life adversity.

This study investigated the association between childhood and young adult adversities and later-life subjective well-being among older male veterans. We also explored whether early-life parent–chil...
Tracheal narrowing in children and adults with mucopolysaccharidosis type IVA: evaluation with computed tomography angiography

Mucopolysaccharidosis type IVA (MPS IVA) is characterized by progressive skeletal dysplasia and respiratory issues with difficult airway management during anesthesia. To characterize tracheal abnormalities in children and adults with MPS IVA including interplay of the trachea, vasculature, bones and thyroid at the thoracic inlet. Computed tomography (CT) angiograms of the chest were analyzed for trachea shape, narrowing and deviation at the thoracic inlet, course of vasculature, bone alignment and thyroid location. The tracheal cross-sectional area was measured at the cervical, thoracic inlet and intrathoracic levels. Thirty-seven patients (mean age: 18.1 years) were included. The mean tracheal cross-sectional area narrowing at the thoracic inlet was 63.9% (range: −2.1–96%), with a trend for increased tracheal narrowing in older children. The trachea was commonly deviated rightward posterior (22/37, 59%). T- or W-shaped tracheas had two times greater tracheal narrowing than D- or U-shaped tracheas (P<0.05). The brachiocephalic artery was tortuous in 35/37 (95%) with direct impingement on the trachea in 24/37 (65%). No correlation was observed between bony thoracic inlet diameter and tracheal narrowing. The thyroid was located in the thoracic inlet in 28/37 (76%) cases, significantly associated with tracheal narrowing (P=0.016). Narrowing, deviation and abnormal shape of the trachea at the thoracic inlet are common in children and adults with MPS IVA, with a trend toward increased narrowing with advancing age in children. A W- or T-shaped trachea is associated with focal tracheal narrowing. Crowding of the thoracic inlet, due to vascular tortuosity and thyroid position, appears to play a major role.
Hypermutated phenotype in gliosarcoma of the spinal cord

Gliosarcoma is a variant of glioblastoma with equally poor prognosis and characterized by mixed glial and mesenchymal pathology. Metastasis is not uncommon but the involvement of the spinal cord is rare, and comprehensive genetic characterization of spinal gliosarcoma is lacking. We describe a patient initially diagnosed with a low-grade brain glioma via biopsy, followed by adjuvant radiation and temozolomide treatment. Nearly 2 years after diagnosis, she developed neurological deficits from an intradural, extramedullary tumor anterior to the spinal cord at T4, which was resected and diagnosed as gliosarcoma. Whole-exome sequencing (WES) of this tumor revealed a hypermutated phenotype, characterized by somatic mutations in key DNA mismatch repair (MMR) pathway genes, an abundance of C>T transitions within the identified somatic single nucleotide variations, and microsatellite stability, together consistent with temozolomide-mediated hypermutagenesis. This is the first report of a hypermutator phenotype in gliosarcoma, which may represent a novel genomic mechanism of progression from lower grade glioma.
H3K4me1-marked Enhancer Activation in Resistant Prostate Cancers Implicates SOX4 and MENIN Inhibition as Therapeutic Strategies

Chromatin elements and regulators play important roles during progression of prostate cancer, however, their involvement in response to therapy is less well understood. Using comprehensive chromatin profiling of patient-derived tumors, we find that enhancer elements marked by H3K4me1 are highly enriched in aggressive therapy-resistant prostate cancers on important resistance-driving genes, such as those involved in FOXA1, NOTCH and TGF-{beta} signaling. Importantly, by targeting H3K4me1-elements through inhibition of the MLL complex, a H3K4 methyltransferase, we reduced the proliferative capacity and H3K4me1-associated loci in enzalutamide-resistant prostate cancer lines. We identify AR, FOXA1, HOXB13 and SOX4 as a subset of core TFs that are critical for establishing transcriptional networks via active enhancer reprogramming during acquisition of resistance to therapy. Knock-down of SOX4 reduced cell proliferation and disrupted the H3K4me1 enhancer landscape, further suggesting a role for this TF in therapy-resistance. Overall, our data implicate H3K4me1-marked enhancers as a key epigenetic feature of therapy-resistance, implicate SOX4 in enhancer reprogramming and suggest use of MLL/MENIN inhibitors as a potential therapeutic strategy in high-grade and locally advanced prostate cancers that do not respond to traditional therapies.
Criteria for Effective and Ethical Evaluation Practice

One of the characteristics of an emerging profession is the public and private concern for issues related to the law, ethics, and professional standards. The concern for these issues focuses on both protecting the consumer and evaluator and producing meaningful evaluations, the results of which are appropriately used.
The Canonization of Islamic Law: A Social and Intellectual History

The Canonization of Islamic Law tells the story of the birth of classical Islamic law in the eighth and ninth centuries CE. It shows how an oral normative tradition embedded in communal practice was transformed into a systematic legal science defined by hermeneutic analysis of a clearly demarcated scriptural canon. This transformation was inaugurated by the innovative legal theory of Muhammad b. Idrīs al-Shāfi'ī (d. 820 CE), and it took place against the background of a crisis of identity and religious authority in ninth-century Egypt. By tracing the formulation, reception, interpretation and spread of al-Shāfi'ī's ideas, the author demonstrates how the canonization of scripture that lay at the heart of al-Shāfi'ī's theory formed the basis for the emergence of legal hermeneutics, the formation of the Sunni schools of law, and the creation of a shared methodological basis in Muslim thought.
Building the Case for Life:A Mitigation Specialist as aNecessity and a Matter of Right

University of Virginia, May 2000. The author is indebted to the members of the Virginia Capital Case Clearinghouse, especially Professor Roger D. Groot, Janice L. Kopec, Whitnan J. Hou, and Joseph Dunn, for their analysis and insights. The author would also like to thank Elissa Weddle for her support and patience throughout this process. The author is dedicating this article to his parents, Dr. Ken Payne and Dr. Catherine Irwin, for their unwavering support of his education and for never questioning his decision not to join the family business. 1. See, e.g., Williams v. Taylor, 529 U.S. 362, 396 (2000) (holding that counsel’s failure to uncover and present voluminous mitigating evidence at sentencing could not be justified as a tactical decision because “trial counsel did not fulfill their obligation to conduct a thorough investigation of the defendant’s background”); Buchanan v. Angelone, 522 U.S. 269, 276 (1998) (holding that, during the penalty phase, “the sentencer may not be precluded from considering . . . any constitutionally relevant mitigating evidence”); McCleskey v. Kemp, 481 U.S. 279, 305–06 (1987) (holding that a constitutional death penalty scheme “cannot limit the sentencer’s consideration of any relevant circumstance that could cause it to decline to impose the [death] penalty”); Strickland v. Washington, 466 U.S. 668, 691 (1984) (holding that “counsel has a duty to make reasonable investigations [into potential defenses] or to make a reasonable decision that makes particular investigations unnecessary”); Eddings v. Oklahoma, 455 U.S. 104, 114 (1982) (holding that a sentencer may not “refuse to consider, as a matter of law, any relevant mitigating evidence”); Green v. Georgia, 442 U.S. 95, 97 (1979) (holding that Georgia’s hearsay rule cannot be invoked to exclude “testimony [that] was highly relevant to a critical issue in the punishment phase of the trial”); Lockett v. Ohio, 438 U.S. 586, 604 (1978) (arguing “that the Eighth and Fourteenth Amendments require that the sentencer . . . not be precluded from considering, as a mitigating factor, any aspect of a defendant’s character or record and any of the circumstances of the offense that the defendant proffers as a basis for a sentence less than death”); Woodson v. North Carolina, 428 U.S. 280, 304 (1976) (holding “that in capital cases the fundamental respect for humanity underlying the Eighth Amendment . . . requires consideration of the character and record of the individual offender and the circumstances of the particular offense as a constitutionally indispensable part of the process of inflicting the penalty of death” (citations omitted)). 2. Wiggins v. Smith, 123 S. Ct. 2527, 2536–37 (2003) (holding that defense counsel, who
Software Approaches for Determination of 3-Dimensional Molecular Structures from Multi-Dimensional NMR

Two and higher dimensional NMR spectroscopies offer extraordinary power for detailed structure elucidation of proteins, nucleic acids and other important biomolecules. The methodology of elucidating biopolymer structures at atomic resolution from NMR spectroscopic data incorporates primarily NOESY experiments, but also may add spin-spin coupling constants and other information measured from COSY and other NMR experimentation. There are several important challenges that must be overcome in order for this methodology to be generally applicable to a broad range of biomolecules. One of the most important long-term goals of this research arena is to be able to determine structures with a confidence level sufficient to allow utilization of the structural information without confirmatory experimentation such as single X-ray structures.