cssi/SciSciGPT-SciSciNet huggingface dataset:
OR30: SUCCESSFUL OUTCOMES OF COMBINED HEART LIVER TRANSPLANTS ACROSS PRE-FORMED HIGH LEVELS OF DONOR SPECIFIC HLA ANTIBODIES

Aim In combined heart liver (CHL) transplants (Txp), it is unclear if the heart would be protected from rejection when pre-Txp donor specific antibodies (DSA) are present since the heart Txp procedure is usually performed a few hours before the liver Txp. We describe 2 cases of a successful CHL Txp across high levels of pre-Txp HLA class I and class II DSA. Methods Patients’ demographics, past medical history, and treatments are shown in Table 1. In case 1, the patient was desensitized pre-Txp and intra-operatively (intra-op) as described in Table 1. Pre- and post-Txp sera were analyzed for IgG and complement-binding DSAs using commercially available single-antigen bead assay kits. Results Both patients had excellent clinical outcomes without any episodes of antibody mediated rejection (AMR) after 1.5 and 4 years of follow up in case 1 and case 2 respectively (Table 1). In case 1, post-Txp anti-HLA antibody measurements showed a near complete depletion of HLA class II IgG DSA 1 day post-Txp, and remained negative thereafter. A significant decrease of HLA class I complement-binding (C1q) DSA was also observed while the decrease of HLA class I IgG DSA was more moderate ( Fig. 1 , Fig. 2 ). A similar depletion of HLA class I and class II DSA was also observed in case 2 (data not shown). Conclusions In 2 cases, a successful CHL Txp was achieved across high levels of pre-Txp HLA class I and class II DSA. Long term outcome was excellent, without any episodes of AMR.
Caveolin-1 Mutations (P132L and Null) and the Pathogenesis of Breast Cancer: Caveolin-1 (P132L) Behaves in a Dominant-Negative Manner and Caveolin-1 (−/−) Null Mice Show Mammary Epithelial Cell Hyperplasia

Caveolin-1 (Cav-1) is the principal structural protein of caveolae membranes that are found in most cells types, including mammary epithelial cells. Recently, we mapped the human CAV1 gene to a suspected tumor suppressor locus (7q31.1/D7S522) that is deleted in a variety of human cancers, as well as mammary tumors. In addition, the CAV1 gene is mutated (P132L) in up to ∼16% of human breast cancers. The mechanism by which deletion or mutation of the Cav-1 gene contributes to mammary tumorigenesis remains unknown. To understand the role of the Cav-1 (P132L) mutation in the pathogenesis of human breast cancers, we generated the same mutation in wild-type (WT) Cav-1 and studied its behavior in cultured cells. Interestingly, the P132L mutation leads to formation of misfolded Cav-1 oligomers that are retained within the Golgi complex and are not targeted to caveolae or the plasma membrane. To examine whether the Cav-1 (P132L) mutant behaves in a dominant-negative manner, we next co-transfected cells with Cav-1 (P132L) and WT Cav-1, and evaluated their caveolar targeting. Our results indicate that Cav-1 (P132L) behaves in a dominant-negative manner, causing the mislocalization and intracellular retention of WT Cav-1. Virtually identical results were obtained when Cav-1 (P132L) was stably expressed at physiological levels in a nontransformed human mammary epithelial cell line (hTERT-HME1). These data provide a molecular explanation for why only a single mutated CAV1 allele is found in patients with breast cancer. Thus, we next investigated if functional inactivation of Cav-1 gene expression leads to mammary tumorigenesis in vivo. For this purpose, we performed mammary gland analysis on Cav-1-deficient mice (−/−) that harbor a targeted disruption of the Cav-1 gene (a null mutation). Interestingly, we show that inactivation of Cav-1 gene expression leads to mammary epithelial cell hyperplasia, even in 6-week-old virgin female mice. These data clearly implicate loss of functional Cav-1 in the pathogenesis of mammary epithelial cell hyperplasia, and suggest that Cav-1-null mice represent a novel animal model to study premalignant mammary disease.
Artificial Intelligence Approaches to Image Understanding

The past decade has seen considerable progress in the development of computer vision within Artificial Intelligence. Attention has shifted from restrictions on the domain of application of a vision system to restrictions on the visual abilities studied. Mathematical analyses have been offered for some of the elements of visual perception, such as the relationship between image irradiance and scene radiance, the location of important intensity changes and motion primitives. In each case, it is observed that the information in the image only partially constrains the interpretation of the image, and further constraints are sought. The constraints embody commitments about the way the world is, at least most of the time. For example, the world mostly consists of smooth surfaces, and scenes are mostly viewed from general position, free of accidental alignments. Perceptual abilities such as stereopsis, lightness determination, shape from shading and from texture, require that the appropriate constraints be uncovered and appropriately expressed. Representations have been developed that make explicit the information computed by a perceptual ability. Examples include the Primal Sketch, the Reflectance Map, and object representations based on generalised cones. The isolation of representations has lead to a view of visual perception as the process of constructing instances of a sequence of representations. The input to a particular process is often not the image per se, but a representation of the information computed by a number of processes. It is this observation which most strongly distinguishes image understanding from conventional pattern recognition. A number of sample image understanding systems are described, including edge detection, shape from shading, binocular and photometric stereo, optical flow, directional selectivity, surface reconstruction through interpolation and the representation of objects by primitive volumes. In some cases, it has been possible to directly relate the theory embodied in the program to animate visual systems. In some cases it has been possible to develop important practical applications for example, industrial inspection and bin picking in robotics, and monitoring airfields or terrain for changes in usage. Finally, in some cases it has been possible to construct hardware realizations of theories to achieve real time performance.
Pediatric Facts, Formulas, and Laboratory Values

In no other area of critical care are formulas as important as in pediatrics. The large variation in patient size requires that simple rules of thumb be available to the critical care practitioner.
Hepatocellular Carcinoma: Etiology and Natural History

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for ∼85% of all cases [1]. Overall, it is the fifth most common cancer worldwide, representing about 5.7% of all new human cancer cases [2]. It also ranks as the third leading cause of cancer-related death in the world [2]. The number of deaths per year due to HCC is almost identical to its incidence, which highlights the poor prognosis and aggressive nature of the cancer [2]. The goal of this chapter is to review the epidemiology, etiologic associations, and natural history of HCC, which poses a significant public health problem in many countries around the world.
Sterol methyltransferase is required for optimal mitochondrial function and virulence in Leishmania major

Limited knowledge on the exact functions of ergostane-based sterols has hampered the application of sterol synthesis inhibitors against trypanosomatid parasites. Sterol methyltransferase (SMT) is directly involved in the synthesis of parasite-specific C24-methylated sterols, including ergosterol and 5-dehydroepisterol. While pharmacological studies hint at its potential as a drug target against trypanosomatids, direct evidence for the cellular function and essentiality of SMT is lacking. Here, we characterized the SMT knockout mutants and their complemented strains in Leishmania major, the causative agent for cutaneous leishmaniasis. Deletion of SMT alleles led to a complete loss of C24-methylated sterols, which were replaced by cholestane-based sterols. SMT-null mutants were fully viable and replicative in culture but showed increased sensitivity to sphingolipid synthesis inhibition. They were not particularly vulnerable to heat, acidic pH, nitrosative or oxidative stress, yet exhibited high mitochondrial membrane potential and increased superoxide generation indicating altered physiology of the mitochondria. Despite possessing high levels of GPI-anchored glycoconjugates, SMT-null mutants showed significantly attenuated virulence in mice. In total, our study reveals that the biosynthesis of ergostane-based sterols is crucial for the proper function of mitochondria and the proliferation of Leishmania parasites in mammals.
Across the Waves: How the United States and France Shaped the International Age of Radio

Derek Vaillant’s book tells a compelling story about the origins of wireless radio from the perspective of two sovereign nations that made maximum use of this new medium for global reporting and ex...
A Curcumin Degradation Product, 7-Norcyclopentadione, Formed by Aryl Migration and Loss of a Carbon from the Heptadienedione Chain

Evidence that anti-inflammatory and other biological effects of curcumin may at least in part be mediated by its metabolites underscores the importance of identifying novel transformation products. Spontaneous degradation of curcumin in buffer pH 7.5 results mainly in dioxygenated products with a characteristic cyclopentadione ring composed of carbons 2 through 6 of the former heptadienedione chain. When analyzing degradation reactions of 4'- O-methylcurcumin, a product was identified missing one of the terminal carbons of the heptadienedione moiety while containing a cyclopentadione ring and adjacent hydroxy group typical of curcumin degradation products. Analysis of curcumin autoxidation reactions showed formation of an analogous compound, 7-norcyclopentadione, a degradation product exhibiting net loss of a carbon and gain of an oxygen atom. Removal of the carbon is proposed to occur via a peroxide-linked curcumin dimer in conjunction with radical-mediated 1,2-aryl migration of a guaiacol moiety. Oxidation reactions of demethoxycurcumin gave demethoxy-7-norcyclopentadione, whereas an analogous product was not observed from bis-demethoxycurcumin. Incubation of RAW264.7 macrophage-like cells with curcumin showed the presence of 7-norcyclopentadione, the formation of which was not increased upon activation of the cells with 12- O-tetradecanoylphorbol-13-acetate . 7-Norcyclopentadione is a novel type of degradation product that is most likely formed via autoxidative processes when cells are incubated with curcumin.
Neuro-Ophthalmic Symptoms of Primary Headache Disorders: Why the Patient With Headache May Present to Neuro-Ophthalmology.

Background:Primary headache disorders can cause many ophthalmic symptoms that lead many patients to present for neuro-ophthalmic evaluation. Neuro-ophthalmologists frequently encounter these patients in clinical practice.Evidence Acquisition:A literature review was completed in PubMed using the foll
School absenteeism in the first decade of education and outcomes in adolescence.

Abstract This study used a prospective longitudinal sample of American children from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (n = 1326) to consider the educational, social, and behavioral correlates of absenteeism. More specifically, this study examined: (a) the extent to which absenteeism in the early elementary school years is associated with absenteeism in the later school years; (b) the degree to which absenteeism in the first decade of children's education is associated with their academic achievement and social-behavioral outcomes at age 15; (c) whether the timing of absenteeism matters for outcomes at age 15; and (d) whether early absenteeism has indirect effects on outcomes at age 15 via later absenteeism. Results indicated that school absenteeism was fairly stable throughout children's educational careers and although few children were chronically absent, children who had a weaker attendance record in the early years, in turn, had weaker attendance later on. Ultimately, absenteeism during the earliest years of school was linked with less optimal academic and social-behavioral outcomes at age 15 because children were more likely to be absent later on in their educational careers.
Identification of potential binding pocket on viral oncoprotein HPV16 E6: a promising anti-cancer target for small molecule drug discovery

Several human cancers, especially cervical cancer are caused by the infection of high risk strains of human papillomaviruses (HPV), notably HPV16. It is implicated that the oncoprotein E6 expressed from HPV, is inhibiting the apoptotic pathway by binding to adaptor molecule FADD (Fas-associated death domain). Inhibiting E6 interactions with FADD could provide a promising treatment for cervical cancer. There are few small molecules reported to inhibit such interactions. However, the FADD binding site information on the HPV E6 is not currently available. This binding site information may provide an opportunity to design new small molecule inhibitors to treat E6 mediated cancers. In this study we report the possible binding pocket on HPV16 E6 oncoprotein by using activity data of reported inhibitors through a stepwise molecular modeling approach. Blind docking and removing duplicates followed by visual inspection to determine ligand-receptor interactions provided 68 possible binding sites on the E6 protein. Individual docking of all known inhibitors lead to the identification of 28 pockets having some kind of correlation with their activity data. It was also observed that several of these pockets overlapped with each other, having some amino acids in common. Amino acids Leu50 and Cys51 were identified as key E6 residues for high affinity ligand binding which are seen in most of these pockets. In most cases, ligands demonstrated a hydrogen bond interaction with Cys51. Ala61, Arg131 and Gln107 were also frequently observed showing interactions among these pockets. A few amino acids unique to each ligand were also identified representing additional interactions at the receptor site. After determining receptor-ligand interactions between E6 oncoprotein and the six known inhibitors, the amino acids Cys51, Leu50, Arg102, Arg131, Leu67, Val62, and Gln107 were identified to have importance in E6 inhibition. It was generally observed that Leu50 and Cys51 are necessary for high binding affinity with Cys51 being essential for hydrogen bonding. This study identified a potential binding pocket for the E6 inhibitors. Identification of the ligand binding pocket helps to design novel inhibitors of HPV16 E6 oncoprotein as a promising treatment for cervical cancer.
Linear Hotspot Discovery on All Simple Paths: A Summary of Results

Spatial hotspot discovery aims at discovering regions with statistically significant concentration of activities. It has shown great value in many important societal applications such as transportation engineering, public health, and public safety. This paper formulates the problem of Linear Hotspot Detection on All Simple Paths (LHDA) which identifies hotspots from the complete set of simple paths enumerated from a given spatial network. LHDA overcomes the limitations of existing methods which miss hotspots that naturally occur along linear simple paths on a road network. To address the computational challenges, we propose a novel algorithm named bidirectional fragment-multi-graph traversal (ASP_FMGT) and two path reduction approaches ASP_NR and ASP_HD. Experimental analyses show that ASP_FMGT has substantially improved performance over state-of-the-art approach (ASP_Base) while keeping the solution complete and correct. Moreover, a case study on real-world datasets showed that ASP_FMGT outperforms existing approaches.
Diagnosis and Treatment Approaches to a "Gummy Smile"

Excessive gingival display or "gummy smile" is a growing concern to dental patients and often considered detrimental to an esthetic smile. Gingival display of more than 4 mm of gingiva is considered by many to be unattractive. The cause of the gummy smile can be multifactorial and must be accurately diagnosed to render appropriate treatment. Factors that contribute to the gummy smile include altered passive eruption, lip length, lip hypermobility, incisal wear/crown length, and vertical maxillary excess and gingival hyperplasia. The purpose of this article is to review the etiology, diagnosis, and surgical approaches in treating the gummy smile.
In reply: Barrett esophagus: Definition, treatment

Dr. Lai points out that the broader definition of Barrett esophagus can include the presence of metaplastic columnar epithelium that replaces the normal stratified squamous epithelium in the distal esophagus. Guidelines of both the American College of Gastroenterology[1][1] and the American
Venous cerebral blood volume mapping in the whole brain using venous-spin-labeled 3D turbo spin echo.

PURPOSE Venous cerebral blood volume (CBVv ) is a major contributor to BOLD contrast, and therefore is an important parameter for understanding the underlying mechanism. Here, we propose a velocity-selective venous spin labeling (VS-VSL)-prepared 3D turbo spin echo pulse sequence for whole-brain baseline CBVv mapping. METHODS Unlike previous CBVv measurement techniques that exploit the interrelationship between BOLD signals and CBVv , in the proposed VS-VSL technique both arterial blood and cerebrospinal fluid (CSF) signals were suppressed before the VS pulse train for exclusive labeling of venous blood, while a single-slab 3D turbo spin echo readout was used because of its relative immunity to magnetic field variations. Furthermore, two approximations were made to the VS-VSL signal model for simplified derivation of CBVv . In vivo studies were performed at 3T field strength in 8 healthy subjects. The performance of the proposed VS-VSL method in baseline CBVv estimation was first evaluated in comparison to the existing, hyperoxia-based method. Then, data were also acquired using VS-VSL under hypercapnic and hyperoxic gas breathing challenges for further validation of the technique. RESULTS The proposed technique yielded physiologically plausible baseline CBVv values, and when compared with the hyperoxia-based method, showed no statistical difference. Furthermore, data acquired using VS-VSL yielded average CBVv of 2.89%/1.78%, 3.71%/2.29%, and 2.88%/1.76% for baseline, hypercapnia, and hyperoxia, respectively, in gray/white matter regions. As expected, hyperoxia had negligible effect (P > .8), whereas hypercapnia demonstrated vasodilation (P << .01). CONCLUSION Upon further validation of the quantification model, the method is expected to have merit for 3D CBVv measurements across the entire brain.
Learning a Spatial Field with Gaussian Process Regression in Minimum Time.

We study an informative path planning problem where the goal is to minimize the time required to learn a spatial field using Gaussian Process (GP) regression. Specifically, given parameters \(0< \epsilon , \delta < 1\), our goal is to ensure that the predicted value at all points in an environment lies within \(\pm \epsilon \) of the true value with probability at least \(\delta \). We study two versions of the problem. In the sensor placement version, the objective is to minimize the number of sensors placed. In the mobile sensing version, the objective is to minimize the total travel time required to visit the sensing locations. The total time is given by the time spent obtaining measurements as well as time to travel between measurement locations. By exploiting the smoothness properties of GP regression, we present constant-factor approximation algorithms for both problems that make accurate predictions at each point. Our algorithm is a deterministic, non-adaptive one and based on the Traveling Salesperson Problem. In addition to theoretical results, we also compare the empirical performance using a real-world dataset with other baseline strategies.
Mitigation of Differential Perturbations in Formation Flying Satellite Clusters

Aperture synthesis using distributed satellite systems opens up new possibilities for space-based surveillance of Earth. However, it brings with it new challenges for maintaining the geometry of the array in the presence of gravitational tidal forces and environmental pertubations. Balancing the aperture synthesis need to place the individual satellites in specific relative positions, with the desire to minimize the propellant consumed to do so, leads to the need for creative techniques which exploit the natural orbital motion of the satellites to maintain the geometry of the array. As a result, a new area of orbital mechanics has emerged which deals specifically with the formation flying of satellite clusters for aperture synthesis. This paper presents a candidate orbital formation for such an aperture. A key factor is the amount of propellant required to simply station-keep, or maintain the formation against the perturbative forces encountered in orbit: passive formation flying. This represents the baseline requirement for the propulsion system, before active cluster maneuvering is even considered. This paper quantifies these perturbative effects, first through dimensional analysis to derive the various scaling laws needed to conduct design trades, and then through a rigorous analysis of a specific formation flying mission: the Air Force space-based radar system (TechSat21). Values of lifetime ΔV and propulsive specific impulse, as well as peak thrust, are calculated for TechSat21 and compared to the levels needed for active cluster formation flying. For passive formation flying of TechSat21, 0.5 cm/sec/orbit of ΔV is required to counteract secular terms arising from environmental perturbations such as differential J2. Periodic variations in relative motion have an amplitude of about 0.12% of the array’s diameter, or 60 cm for a 500 m array, if left unchecked. For a required seven year life, with less than 7% propellant fraction, the needs of active formation flying are prohibitively large, and it is shown that an additional 500 seconds of specific impulse are needed for each 1 cm/sec/orbit of ΔV added.
Use of Cannabinoids for the Treatment of OSA

Obstructive sleep apnea (OSA) is associated with increased risk of morbidity and mortality. Positive airway pressure (PAP) therapy remains the gold standard treatment, but its use is often limited by patient compliance, hence the need to consider other potential therapies. Preliminary data may suggest potential role of cannabinoids in the treatment of OSA. We aim to summarize the current knowledge on cannabinoid use and its impact on the pathophysiology of OSA as well as its role as a potential management option. Recently, a phase II placebo-controlled trial of dronabinol reported dose-dependent reduction in the apnea-hypopnea index (AHI). A phase III trial exploring this link further is planned. Cannabinoid use has variable effects in the treatment of OSA. Preliminary data are promising but insufficient regarding both efficacy and safety. Further research is needed to understand its role in management of OSA.
Model of Deep Nonvolcanic Tremor Part II: Episodic Tremor and Slip

Abstract Bursts of tremor accompany a moving slip pulse in episodic tremor and slip (ETS) events. The sources of this nonvolcanic tremor (NVT) are largely unknown. We developed a model describing the mechanism of NVT generation. According to this model, NVT is a reflection of resonant‐type oscillations excited in a fault at certain depth ranges. From a mathematical viewpoint, tremor (phonons) and slip pulses (solitons) are two different solutions of the sine‐Gordon equation describing frictional processes inside a fault. In an ETS event, a moving slip pulse generates tremor due to interaction with structural heterogeneities in a fault and due to failures of small asperities. Observed tremor parameters, such as central frequency and frequency attenuation curve, are associated with fault parameters and conditions such as elastic modulus, effective normal stress, penetration hardness, and friction. Model prediction of NVT frequency content is consistent with observations. In the framework of this model, it is possible to explain the complicated pattern of tremor migration, including rapid tremor propagation and reverse tremor migration. Migration along the strike direction is associated with movement of the slip pulse. Rapid tremor propagation in the slip‐parallel direction is associated with movement of kinks along a 2D slip pulse. A slip pulse, pinned in some places, can fragment into several pulses, causing tremor associated with some of these pulse fragments to move opposite to the main propagation direction. The model predicts that the frequency content of tremor during an ETS event is slightly different from the frequency content of ambient tremor and tremor triggered by earthquakes.
Sex Difference in the Association between Electronic Cigarette Use and Subsequent Cigarette Smoking among U.S. Adolescents: Findings from the PATH Study Waves 1-4.

E-cigarettes are the most-used tobacco products among U.S. adolescents. Emerging evidence suggests that adolescents using e-cigarettes are at elevated risk for initiating cigarette smoking. However, whether this risk may differ by sex remains unknown. This study analyzed data from Wave 1 to 4 of the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative longitudinal survey. Generalized estimation equations (GEE) were performed to estimate the associations between baseline e-cigarette use and subsequent cigarette smoking, controlling for sociodemographic characteristics, mental health conditions, and other tobacco use. Effect modifications by sex were examined. Multivariate analyses showed that, among baseline never cigarette smokers, past-30-day e-cigarette use at baseline waves was significantly associated with past-30-day cigarette smoking at follow-up waves (aOR = 3.90, 95% CI: 2.51–6.08). This association was significantly stronger for boys (aOR = 6.17, 95% CI: 2.43–15.68) than for girls (aOR = 1.10, 95% CI: 0.14–8.33). Additionally, using other tobacco products, older age, and having severe externalizing mental health problems at baseline were significantly associated with an increased likelihood of cigarette smoking at follow-up. The prospective association between e-cigarette use and cigarette smoking differs by sex among U.S. adolescents. Sex-specific tobacco control interventions may be warranted to curb the youth tobacco use epidemic.
Soil health spatial-temporal variation influence soil security on Midwestern, U.S. farms

Abstract Soil security is a multifaceted framework that considers soil as an integral part of addressing societal concerns towards global environmental challenges. Soil health assessments are tools that can be used to integrate knowledge about and social interest in soil resource sustainability. Appropriate interpretation of soil health assessments require robust databases of soil properties and their variation across large regional areas. This analysis explored field-scale spatial and temporal variation in 16 soil health indicators used in common soil health assessments at Soil Health Partnership (SHP) locations throughout the Midwestern U.S. from 2014–2019. Relationships among management, environment, and measured soil properties were examined using various combinations of correlation, principal component analysis (PCA), and multiple regression. Specifically, variability was evaluated using 1) the temporal average of indicator lab test values, 2) the temporal and spatial coefficient of variation (CV), and 3) corn (Zea mays) and soybean (Glycine max) yield variation. Solvita® had the highest spatial and temporal CV, while organic matter (OM), autoclaved citrate extractable protein (ACE), and pH had the lowest spatial and temporal CV values. The PCA analysis identified climate, soil texture, organic C and N pools, and soil water availability as factors that accounted for variation in soil health indicator values. Multiple regression showed that climate variables and field conditions strongly affect corn and soybean yield variation. Solvita, OM, and available water content improved corn and soybean yield variation estimates. These results show that considering spatial and temporal variation when monitoring soil health changes may improve soil health assessment interpretation.
Local Elites and Public Good Provision: Evidence From the Rise of Public Education in the Early 20th Century China

Do social elites facilitate public good provision? Public primary education in China only started after 1905, and it expanded rapidly in the following three decades. This paper studies the infancy stage of the public education system in China and focuses specifically on the role of its most important local elite group — lower degree holders under the civil service exam system. I construct a new county-level dataset linking local elites to public education provision. I find counties that had larger elite groups built significantly more public primary schools and spent higher expenditure on education. This finding is robust to various checks, including two IV approaches. Furthermore, the positive effect of local elites was larger in counties with the weaker formal ruling, proxied by both high frequent turnover of local magistrates and distance to provincial capital. These results suggest that the informal governance imposed by local elites was critically important for the provision of public goods, especially in societies where the formal ruling was weak.
Models of Care

Cancer care has become increasingly specialized, and advances in treatment have resulted in a larger proportion of cancer patients receiving treatment as outpatients. Although there are many cancer centers throughout the world that are dedicated solely to the care of cancer, there are few centers that specialize in the emergent care of these patients in the United States. In this chapter, we describe different models of care for oncologic emergencies, as well as common treatment needs and challenges of treating this population. The models range from EDs at large, dedicated cancer centers (The University of Texas MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center, USA) to specialized pods housed within larger, more traditional EDs (The Ohio State University Wexner Medical Center, USA).
Model-informed precision dosing for alemtuzumab in paediatric and young adult patients undergoing allogeneic haematopoietic cell transplantation.

Aim Alemtuzumab is a lymphodepleting monoclonal antibody utilized in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). A recently proposed therapeutic range of 0.15-0.6 μg/mL on the day of transplantation is associated with better HCT outcomes. The purpose of this study was to characterize alemtuzumab population pharmacokinetic/pharmacodynamic (PK/PD) and to propose individualized subcutaneous dosing schemes to achieve this optimal level for pediatric patients. Methods Alemtuzumab concentration and absolute lymphocyte count (ALC) profiles were obtained from 29 pediatric and young adult patients (median age 6.4 years; range 0.28 - 21.4 years) with non-malignant disorders undergoing HCT. PK/PD analyses were performed using non-linear mixed effects modeling. Monte Carlo simulation was conducted to evaluate different improved dosing approaches. Results A one-compartment model with sequential zero- and first-order absorption adequately described subcutaneously administered alemtuzumab PK. Model fit was significantly improved by including allometrically scaled body weight on clearance (0.080 L/h/70kg) and volume of distribution (17.4 L/70kg). ALC reduction following subcutaneous alemtuzumab was swift. An inhibitory Emax model best characterized the relationship between alemtuzumab concentration and ALC. Emax and EC50 were estimated as 1.18*103 /μL and 0.045μg/mL, respectively. The currently used per kg dosing was found to cause uneven alemtuzumab exposure across different age and weight cohorts. Simulations indicated optimal target achieving dose as allometry-based dose of 18 mg*(weight/70)0.75 or body surface area (BSA)-based dose of 10 mg/m2 , divided over 3 days, with a potential individualized top-up dose; both of which yielded similar results. Conclusion An allometry- or BSA-based starting dosing regimen in combination with individualized Bayesian PK estimation using concentration feedback is proposed for alemtuzumab precision dosing in children undergoing allogeneic HCT.
Random peptides rich in small and disorder-promoting amino acids are less likely to be harmful

Proteins are the workhorses of the cell, yet they carry great potential for harm via misfolding and aggregation. Despite the dangers, proteins are sometimes born de novo from non-coding DNA. Proteins are more likely to be born from non-coding regions that produce peptides that do little to no harm when translated than from regions that produce harmful peptides. To investigate which newborn proteins are most likely to "first, do no harm", we estimate fitnesses from an experiment that competed Escherichia coli lineages that each expressed a unique random peptide. A variety of peptide metrics significantly predict lineage fitness, but this predictive power stems from simple amino acid frequencies rather than the ordering of amino acids. Amino acids that are smaller and that promote intrinsic structural disorder have more benign fitness effects. We validate that the amino acids that indicate benign effects in random peptides expressed in E. coli also do so in an independent dataset of random N-terminal tags in which it is possible to control for expression level. The same amino acids are also enriched in young animal proteins.
Signaling inflammation across the gut-brain axis.

The brain and gastrointestinal tract are critical sensory organs responsible for detecting, relaying, integrating, and responding to signals derived from the internal and external environment. At t...
Chapter 18 Osteoarthritis as a Target for Drug Intervention

Publisher Summary Osteoarthritis (OA) is the most frequent of all mammalian joint diseases and produces significant morbidity. The disease is majorly age dependent and certain types of OA show a hereditary disposition. OA may be limited to one joint, although often several joints are involved and sometimes the disorder is generalized. Pain is the cardinal symptom of OA, initially being associated with motion but eventually persisting even at rest. Other symptoms include localized stiffness, tenderness, crepitus, and mild joint enlargement. Cartilage changes include surface disruption and ulceration. Gross bone deformity is associated with advanced disease and synovial changes occur. Current chemotherapy of OA centers on the relief of pain. The chronic use of steroidal and nonsteroidal anti-inflammatory agents in this context continues to cause concern over the long-term effect of some of these agents on joint tissues. As the factors underpinning the deterioration of joint structures become clearer, the opportunities to modify rationally the disease process with drugs is likely to increase. Also as new theories emerge to explain changes in the molecular biology in OA, medicinal chemistry is anticipated to provide the potential to probe these theories with the hope of providing therapeutic utility. Novel enzyme inhibitors may prove to be the most effective way of evaluating the roles of various enzymes in OA as the activities of such enzymes are low, but devastating, over a period of time.
Latent Class Analysis of Early Developmental Trajectory in Baby Siblings of Children with Autism

Background Siblings of children with autism (sibs-A) are at increased genetic risk for autism spectrum disorders (ASD) and milder impairments. To elucidate diversity and contour of early developmental trajectories exhibited by sibs-A, regardless of diagnostic classification, latent class modeling was used.
Comparative Environmental Law Perspectives on Legal Regimes for Sustainable Development

Environmental law, evaluated across nations through the techniques of comparative law, is both a foundation for sustainable development in terms of Agenda 21 and serves as an indicator of the success or failure of a nation's measures to attain or maintain sustainable development. The systematic analysis of environmental law in this way is still in its infancy, and much more attention has been devoted to international environmental law. This is partially because it is difficult to know how to compare Environmental Law and where to find it in different jurisdictions. By clarifying the processes of comparative environmental legal study, the objectives of sustainable development can be materially advanced.
Hauling Containers: Port Drayage Drivers in the Logistics Supply Chain

With the globalization of production, the goods-moving sector of the economy has increasing significance.Over half of all imported goods consumed in the U.S. arrive by container ship and are largely moved from the port terminal to the next point in the supply chain by truck. This “port drayage” system employs drivers that work under a particular set of conditions. We look more closely at this sector of the logistics labor force. We replicate and extend studies done on port drayage workers at other U.S. ports based on a survey distributed to port truckers in Jacksonville, Florida. Our quantitative and qualitative results confirm prior studies regarding the most significant work-related challenges facing drivers. These include levels and methods of compensation, delays and bottlenecks, unsafe chassis, and treatment by terminal workers. Finally, we make policy recommendations for improving both the quality of the work and the efficiency of the logistics supply chain.
Radial migration of DNA molecules in cylindrical flow. II. The non-draining model and possible application to fractionation.

Abstract The radial-migration calculation of the preceding paper is extended to the non-draining polymer. The results show an inward radial velocity that depends on the 5/2 power of the molecular weight, assuming gaussian statistics for the chain. This sensitivity to size serves as the basis for a method of separating DNA molecules in solution according to their size. Normal stress (Weissenberg) effects are also discussed.
Mutations in DNA Mismatch Repair Genes Are Not Responsible for Microsatellite Instability in Most Sporadic Endometrial Carcinomas

Endometrial carcinoma is the second most common tumor type in women with hereditary nonpolyposis colorectal carcinoma. Microsatellite instability (MI) has been observed in the inherited (hereditary nonpolyposis colorectal carcinoma-associated) form of endometrial carcinoma as well as in approximately 20% of presumably sporadic cases. Recent studies suggest that MI in many cell lines or xenografts derived from sporadic colorectal carcinomas is not attributable to mutations in four known human DNA mismatch repair (MMR) genes (hMSH2, hMLH1, hPMS1, and hPMS2). Mutational analyses of these four MMR genes in endometrial carcinomas have not been previously reported. We analyzed nine sporadic MI-positive primary endometrial carcinomas for mutations in the above four MMR genes. Mutations were detected in two tumors (in hMSH2), and both of the mutations were acquired somatically. Immunohistochemical staining revealed a lack of expression of hMSH2 protein in the two tumors containing hMSH2 mutations. Our data suggest that mutations in these four known DNA MMR genes are not responsible for MI in the majority of sporadic endometrial carcinomas displaying this phenotype.
Formation of a new derivative of secondary amines during trimethylsilylation with n,o-bis(trimethylsilyl)-fluoroacetamide

Abstract Trimethylsilylation of secondary amines by the common reagent N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) in the presence of dimethylformamide (DMF) produces the previously unknown N-(aminomethylene)-2,2,2-triftuoroacetamide (AMT) derivative, in addition to the trimethylsilyl derivative. This derivative is formed in varying yield by incorporation of CH atoms from DMF, and a CF 3 CO group from BSTFA. The structure of the AMT moiety was characterized in the nucleic acid base queuine using stable isotopic labeling, high-resolution mass spectrometry, and 13 C and 19 F nuclear magnetic resonance spectroscopy. The AMT derivative has unexplored potential for use in gas chromatography and mass spectrometry but its formation may otherwise be undesirable, suggesting that the combined use of BSTFA and DMF be used with caution for silylation of compounds containing secondary amino groups.
Initiation of the infection process by Erysiphe graminis : conversion of the conidial surface from hydrophobicity to hydrophilicity and influence of the conidial exudate on the hydrophobicity of the barley leaf surface

Abstract When conidia of Erysiphe graminis are produced, they are hydrophobic and float when placed on the surface of a water droplet. In the hydrophobic state, a conidium may form one or more short germ tubes but fails to form an appressorial germ tube. Formation of an appressorial germ tube, from which the appressorium develops, is required for the establishment of the fungus as a pathogen on leaves of its barley host. Appressorial germ tube formation appears to require conversion of the conidium surface from a hydrophobic to a hydrophilic state. The present investigation shows that this conversion coincides with the contact-stimulated release of a liquid exudate from the conidium. Once the exudate is released, a conidium sinks when placed on water, indicating that it has become relatively more hydrophilic. When hydrophilic conidia are placed on cellophane or the surface of barley leaves, they undergo morphogenesis leading to the formation of appressoria. Incubation of the conidial liquid exudate on the hydrophobic surface of a barley leaf caused the leaf surface to become more hydrophilic. It is suggested that this phenomenon promotes the contact of the conidium with the leaf surface and establishes conditions required for a conidium to germinate by the formation of an appressorial germ tube.
Parametric Optimization: Response Surfaces and Neural Networks

This chapter will discuss one of the oldest simulation-based methods of parametric optimization — namely, the response surface method. For simulation-optimization purposes, the response surface method (RSM) is admittedly primitive. But it will be some time before it moves to the museum because it is a very robust technique that often works well when other methods fail. It hinges on a rather simple idea — that of obtaining an approximate form of the objective function by simulating the system at a finite number of points, which are carefully sampled from the function space. Traditional RSM usually uses regression over the sampled points to find an approximate form of the objective function.
Persistence of tree related patterns in soil nutrients following slash-and-burn disturbance in the tropics

Individual trees are known to influence soil chemical properties, creating spatial patterns that vary with distance from the stem. The influence of trees on soil chemical properties is commonly viewed as the agronomic basis for low-input agroforestry and shifting cultivation practices, and as an important source of spatial heterogeneity in forest soils. Few studies, however, have examined the persistence of the effects of trees on soil after the pathways responsible for the effects are removed. Here, we present evidence from a Mexican dry forest indicating that stem-related patterns of soil nutrients do persist following slash-and-burn removal of trees and two years of cropping. Pre-disturbance concentrations of resin extractable phosphorus (P), bicarbonate extractable P, NaOH extractable P, total P, total nitrogen (N) and carbon (C), KCl extractable nitrate (NO3 -), and net N mineralization and nitrification rates were higher in stem than dripline soils under two canopy dominant species of large-stemmed trees with contrasting morphologies and phenologies (Caesalpinia eriostachys Benth. and Forchhammeria pallida Liebm.). These stem effects persisted through slash burning and a first growing season for labile inorganic and organic P, NaOH inorganic P, and plant-available P, and through a second growing season for labile organic P, NaOH organic P, and plant-available P. While stem effects for extractable NO3 -, net nitrification rates, total N and C disappeared after felling and slash burning, these stem effects returned after the first growing season. These results support the view that tree-influenced patterns of soil nutrients do persist after tree death, and that trees contribute to the long-term spatial heterogeneity of forest soils.
Nanoelectronic-Based Detection for Biology and Medicine

This chapter is a review of the work in nanoelectronic detection of biological molecules and its applications in biology and medicine. About half of the chapter focuses on the methods employed to immobilize deoxyribonucleic acid (DNA) on solid substrates with particular focus on the electronic detection and characterization of DNA. Charge-transfer properties and theories are explained, as such electronic and electrical sensing of molecular-level interactions are very important in medical applications for rapid and cheap diagnosis.
Immigrants’ Perceptions of the Police

Despite a fast growing immigrant population and the recent intensive debate over immigration law enforcement, research on police-immigrant relations in general and immigrants’ perceptions of the police in particular remains limited. This article comprehensively reviews existing literature on immigrants’ perceptions of the police. It starts with the value and timeliness of studying immigrants’ attitudes and expectations of the police in today’s multi-racial, multi-cultural society. Then the article summarizes findings regarding how immigrants perceive the police and what factors shape their perceptions. Evidence about the effects of both universal factors and factors unique to immigrants on their perceptions of the police is presented. The article concludes with a brief discussion of future research.
Improved detection of simian immunodeficiency virus RNA by in situ hybridization in fixed tissue sections: combined effects of temperatures for tissue fixation and probe hybridization.

Abstract In situ hybridization detection of viral RNAs in formaldehyde-fixed tissue specimens is used frequently to characterize the extent of viral replication within host tissues. The ability to determine the level of expression of viral RNAs in situ is dependent upon many factors including the extent of cross-linking during fixation, the pretreatment regimen utilized to relieve the effects of cross-linking, and the hybridization and wash protocols. In efforts to improve our ability to detect cells infected productively by simian immunodeficiency virus (SIV) in rhesus macaque tissues, the effects of unconventionally high (40 °C) and more standard low (4 °C) temperature fixation in 4% paraformaldehyde/phosphate buffered saline were tested empirically on in situ hybridization signals. In addition, hybridization temperatures ranging between 37 and 75 °C were utilized to determine the optimal hybridization conditions for detection of SIV productively infected cells. Fixation conditions of 40 °C and hybridization conditions of 50–55 °C were identified as providing the greatest sensitivity for detecting RNA+ cells and for quantitating the signal per cell, while still allowing antigenic epitopes to be detected by immunohistochemical staining. These data indicate that the signal intensity following in situ hybridization for viral RNAs is dependent upon the combined effects of tissue fixation and in situ hybridization temperatures.