cssi/SciSciGPT-SciSciNet huggingface dataset:
The triallelic serotonin transporter gene polymorphism is associated with depressive symptoms in adults with chronic pain.

BACKGROUND The serotonin (5-HT) transporter-linked polymorphic region (5-HTTLPR) moderates the relationship between stressful life events and depression. Given the high prevalence of depression in chronic pain, the primary aim of this preliminary study was to investigate the associations between the 5-HTTLPR and the severity of depressive symptoms in a cohort of adults with chronic pain. METHODS Adults with chronic pain who were consecutively admitted to an outpatient pain rehabilitation program and met inclusion criteria were recruited for study participation (n=277). Individuals were genotyped for the 5-HTTLPR (including rs25531) and categorized as high, intermediate, or low expressors of the 5-HT transporter. The severity of depressive symptoms at admission was measured by using the Center for Epidemiologic Depression scale (CES-D). RESULTS The distribution of the high-, intermediate-, and low-expressing genotypes was 61 (22%), 149 (54%), and 67 (24%), respectively. The Hardy-Weinberg P-value was 0.204, which indicated no departure from equilibrium. A main effect of 5-HTTLPR was observed for depressive symptoms (P=0.040) where Center for Epidemiologic Depression scale (CES-D) scores were significantly greater in the low-expressing group compared to the high- (P=0.019) and intermediate (P=0.029)-expressing groups. In multivariate multinomial logistic regression analysis adjusted for age, sex, pain severity, pain catastrophizing, and pain anxiety, greater CES-D scores were significantly associated with the 5-HTTLPR low-expressing group compared to the high-expressing group (P=0.023), but not for the low-expressing group compared to the intermediate-expressing group (P=0.056). CONCLUSION These preliminary findings suggest that the triallelic 5-HTTLPR could influence the severity of depressive symptoms in adults with chronic pain. Individuals with chronic pain may be particularly vulnerable to the moderating effects of 5-HTTLPR due to high levels of pain-related stress that are inherently present in this population.
Sydenham's chorea. Clinical and therapeutic update.

First described in the late 1600’s as St. Vitus’ dance, Sydenham’s chorea (SC) is now known to be a major manifestation of rheumatic fever. From the 1960’s onward, mirroring the decline in the incidence of rheumatic fever, the number of SC cases fell dramatically worldwide. Over the past decade, however, there appears to have been a resurgence of the disorder, mainly localized to the United States10. The renewed interest in post-streptococcal chorea has been fortuitous, deepening our understanding of the role of the basal ganglia in both disorders of motor control and in neuropsychiatric diseases. This chapter reexamines the clinical features of this interesting disorder and reviews the recent developments in treatment.
Why Enveloped Viruses Need Cores-The Contribution of a Nucleocapsid Core to Viral Budding.

Abstract During the lifecycle of many enveloped viruses, a nucleocapsid core buds through the cell membrane to acquire an outer envelope of lipid membrane and viral glycoproteins. However, the presence of a nucleocapsid core is not required for assembly of infectious particles. To determine the role of the nucleocapsid core, we develop a coarse-grained computational model with which we investigate budding dynamics as a function of glycoprotein and nucleocapsid interactions, as well as budding in the absence of a nucleocapsid. We find that there is a transition between glycoprotein-directed budding and nucleocapsid-directed budding that occurs above a threshold strength of nucleocapsid interactions. The simulations predict that glycoprotein-directed budding leads to significantly increased size polydispersity and particle polymorphism. This polydispersity can be explained by a theoretical model accounting for the competition between bending energy of the membrane and the glycoprotein shell. The simulations also show that the geometry of a budding particle leads to a barrier to subunit diffusion, which can result in a stalled, partially budded state. We present a phase diagram for this and other morphologies of budded particles. Comparison of these structures against experiments could establish bounds on whether budding is directed by glycoprotein or nucleocapsid interactions. Although our model is motivated by alphaviruses, we discuss implications of our results for other enveloped viruses.
Dielectric breakdown field of strained silicon under hydrostatic pressure

First-principles density functional theory calculations are used to reveal a quantitative relationship between the dielectric breakdown field and hydrostatic pressure of crystalline Si. The electronic band structure, phonon dispersion, and electron scattering rate are computed for pressures from 62.2 kbar (compressive) to -45.6 kbar (tensile) to estimate the rate of kinetic energy gain and loss for the electron. The theoretical dielectric breakdown fields are then determined using the von Hippel–Frohlich criterion. Compressive stresses lead to a lower breakdown field, while significant increases in the dielectric breakdown field can be achieved by tensile stresses.
Granzyme A in human platelets regulates the synthesis of proinflammatory cytokines by monocytes in aging

Dysregulated inflammation is implicated in the pathobiology of aging, yet platelet-leukocyte interactions and downstream cytokine synthesis in aging remains poorly understood. Platelets and monocytes were isolated from healthy younger (age <45, n = 37) and older (age ≥65, n = 30) adults and incubated together under autologous and nonautologous conditions. Synthesis of inflammatory cytokines by monocytes, alone or in the presence of platelets, was examined. Next-generation RNA-sequencing allowed for unbiased profiling of the platelet transcriptome in aging. Basal IL-8 and MCP-1 synthesis by monocytes alone did not differ between older and younger adults. However, in the presence of autologous platelets, monocytes from older adults synthesized greater IL-8 (41 ± 5 versus 9 ± 2 ng/ml, p < 0.0001) and MCP-1 (867 ± 150 versus 216 ± 36 ng/ml, p < 0.0001) than younger adults. Platelets from older adults were sufficient for upregulating the synthesis of inflammatory cytokines by monocytes. Using RNA-sequencing of platelets followed by validation via RT-PCR and immunoblot, we discovered that granzyme A (GrmA), a serine protease not previously identified in human platelets, increases with aging (∼9-fold versus younger adults, p < 0.05) and governs increased IL-8 and MCP-1 synthesis through TLR4 and caspase-1. Inhibiting GrmA reduced excessive IL-8 and MCP-1 synthesis in aging to levels similar to younger adults. In summary, human aging is associated with changes in the platelet transcriptome and proteome. GrmA is present and bioactive in human platelets, is higher in older adults, and controls the synthesis of inflammatory cytokines by monocytes. Alterations in the platelet molecular signature and signaling to monocytes may contribute to dysregulated inflammatory syndromes in older adults.
El problema de la conciencia para la filosofía de la mente y de la psiquiatría

Psychiatrists often encounter patients whose symptoms include disorders or impair­ments of consciousness. Unfortunately, the meaning of the term consciousness is not altogether clear. This article presents a systematic review of various meanings attrib­uted to this term, as well as of diverse associated philosophical problems. Likewise, it reconstructs some philosophical and scientific theories of consciousness, identifying their advantages and disadvantages. Finally, it offers some suggestions for the use of the term consciousness in psychiatry.
Non-Local Elasticity and the Line Crack Problem

Further evidence is given to show that the classical line crack problem formulated for non-local elastic media with “smooth” moduli may have no solution with non-infinite crack opening displacements. In particular, claims of finite crack tip stresses, etc., with this theory are likely to be incorrect. We give numerical results which support our earlier theoretical conclusions [1,2]. Computations are made for a modulus which has an elastic component as well as the “smooth” non-local moduli referred to above.
Sanctity of Life: A Study in Ambiguity and Confusion

Bioethics is a field that has defined itself in moral controversies. For example, bioethics has emerged as a discipline in the attempts to resolve moral controversies surrounding medical practices and health care policies in areas such as experimentation and research, abortion, reproduction, and the allocation of resources in health care. One source of constant moral controversy has been the issues surrounding death and dying. There have been controversies about the definition of death, the extent of the obligation to treat the dying, the use of resources for the care of the dying, euthanasia, and assisted suicide. From the celebrated cases in the United States of Karen Ann Quinlan and Nancy Beth Cruzan to the ruling on assisted suicide in the state of Washington (see, Compassion in Dying) the controversies of death and dying have been part of bioethics and public policy.
Regulation of Leydig Cell Cholesterol Metabolism

Steroidogenic tissues have special requirements for cholesterol, which is used as a substrate for tissue specific steroid biosynthesis. Because of this, all steroidogenic tissues, including Leydig cells, have evolved multiple cholesterol delivery pathways and an efficient intracellular cholesterol transport system to ensure constant supply and adequate availability of cholesterol. There are four potential sources, which could contribute to the putative “cholesterol pool” needed for steroidogenesis: (a) de novo synthesized cholesterol, (b) stored cholesteryl esters, (c) exogenous lipoprotein-supplied cholesterol, and (d) plasma membrane-derived cholesterol. Among these, the cholesterol-rich plasma lipoproteins are often the most utilized source of cholesterol for steroid production. Cells acquire lipoprotein-cholesterol both by classic LDL receptor-mediated endocytosis and by selective uptake pathways. In the latter case, lipoprotein cholesteryl ester is selectively internalized without the concomitant uptake and lysosomal degradation of the entire lipoprotein particle. This bulk cholesterol delivery pathway is mediated by a scavenger receptor class B, type-I protein, which is highly expressed and hormonally regulated in steroidogenic cells. In addition to an adequate supply of intracellular cholesterol, steroidogenic cells also require efficient and controlled delivery of cholesterol to outer mitochondrial membranes, and subsequently, to inner mitochondrial membranes for P450scc catalyzed pregnenolone production—the precursor product for all steroids. Although, the exact steps involved in intracellular cholesterol transport to the outer mitochondrial membrane are not yet defined, it appears that vesicular/nonvesicular (through carrier protein) transport processes and interactions between mitochondria, and lipid droplets are probably involved. Two highly studied proteins, peripheral-type benzodiazepine receptor, and steroidogenic acute regulatory protein/steroidogenic acute regulatory protein D1, may function individually, or in concert, to subsequently facilitate the transfer of cholesterol from the outer to inner mitochondrial membranes—the rate-limiting step in steroidogenesis. The present chapter highlights the current understanding of these critical events in Leydig cells; i.e., the acquisiton, intracellular processing, transport, and utilization of cholesterol as the substrate for testosterone production.
Music Treatment for Anhedonia in Major Depressive Disorder: Implications for Therapeutic Interventions

This is a literature review examining the prospect of music as a treatment for anhedonia in major depressive disorder. It delves into the neural circuitry and neurological basis for pleasure, music, and anhedonia. Using the literature, it then explores the relationship among the three and the implications that these connections could have.
Financial Regulation: Still Unsettled a Decade After the Crisis

A decade after the darkest moments of the financial crisis, both the US financial system and the legal framework for its regulation are still in flux. The post-crisis regulatory framework has made systemically important banks much more resilient. They are substantially better capitalized and less dependent on runnable short-term funding. But the current regulatory framework does not deal effectively with threats to financial stability outside the perimeter of regulated banking organizations, notably from forms of shadow banking. Moreover, with the political tide having for the moment turned decisively toward deregulation, there is some question whether the resiliency improvements of the largest banks will be preserved. This article assesses the accomplishments, unfinished business, and outstanding issues in the post-crisis approach to prudential regulation.
Pelvic Fractures and Indications for Pelvic Packing: An Update

Patients with hemodynamically unstable pelvic fractures have a high mortality from pelvic hemorrhage. The purpose of this paper is to review preperitoneal pelvic packing (PPP) as an approach for these patients, including recent outcomes, and evaluation of treatment algorithms including angioembolization and resuscitative endovascular balloon occlusion of the aorta (REBOA). There are no randomized clinical trials comparing PPP to other methods for controlling pelvic hemorrhage. The largest retrospective series, reporting on 128 patients, had a mortality rate of 21% and showed a reduction of blood transfusions after external fixation and PPP; smaller series and a meta-analysis also demonstrate similar results. PPP with external pelvic fixation should be adopted as the first-line intervention for patients with pelvic fractures who remain hemodynamically unstable despite blood transfusion. It takes a lesser time to achieve hemorrhage control than angioembolization and directly addresses the primary source of pelvic fracture-related bleeding.
Screening for Upper Respiratory Tract Cancer. Sputum Cytologic Diagnosis

Screening for cancer is a common issue for debate because few, if any, evaluations of the screening process have been conducted on a long-term, prospective basis with use of concomitant, unscreened controls. Periodic sputum cytology has been incorporated in screening programs designed to detect presymptomatic lung cancer in chronic smokers of excessive numbers of cigarettes (National Cancer Institute 1975; Neel et al. 1981; Sanderson and Fontana 1975; Taylor and Fontana 1972; Taylor et al. 1981). Cytologic examination has led to identification of cancers in the upper respiratory and alimentary tracts of the head and neck region. This observation comes as no surprise, because cigarette smoking is an etiologic factor common to both upper and lower respiratory tract cancers.
Maxwell’s Equations

To describe the electromagnetic behavior of an eddy-current probe coil, and with the goal of becoming equipped to interpret the measured impedance of an eddy-current coil, this chapter describes expressions of Maxwell’s equations in full and under the quasi-static regime that is of direct relevance to eddy-current NDE. From Maxwell’s equations, equations governing the electromagnetic fields can be expressed in various ways. Interface conditions on the electromagnetic field is also provided. The interface conditions are needed, along with the governing equations, to set up a bounded system of equations that can be solved for the fields generated by eddy-current probe coils. Similarly, suitable governing equations and appropriate interface conditions provide the mathematical framework by which the influence of a test-piece—with or without a defect—on the probe impedance can be described.
Reflections on Directions in Health Education: Implications for Policy and Practice. AAHE Scholar Address Revisited - Fast Forward 30 Years

ABSTRACTThe purpose of this paper is to update and enhance the 1989 Association for Health Education (AAHE) Scholar presentation, Reflections on Directions in Health Education: Implications for Pol...
Challenges in Safety Management for New Anticancer Drug: Perspectives from a Pharmaceutical Company

ABSTRACT When developing new drugs, its efficacy and safety data are accumulated throughout the progress of the development phases. Pharmaceutical companies are intrinsically making efforts to examine information related to efficacy and safety of drugs obtained from the clinical trials, reflect them in the package insert and materials for proper use, and provide them to HCPs. However, it was also pointed out that post marketing risk management is conducted only after safety issues occur. In April 2011, risk management plan (RMP) guidance (draft) was released as a guidance when pharmaceutical companies consider further surveillances and studies regarding the safety of the product and additional actions to mitigate risks in the time of new drug application review and the post-marketing phase, and the Ministry of Health, Labour and Welfare (MHLW) called for 'Public Comments' (voice of the people) on its website. In European countries, RMP, which is a mandatory requirement when applying new drugs, plays focal role in risk management and is expected to contribute enhancement of systematic risk management. Before RMP guidance (Draft) announced last year, Eli Lilly Japan, K.K., started to plan its RMP activities in accordance with EU RMP for continuous actions to evaluate and mitigate risks. As an example I would like to explain about an anticancer drug, Alimita (pemetrexed) RMP, which was constructed when approved for malignant pleural mesothelioma (MPM) in 2007 and additionally for non-small cell lung cancer (NSCLC) in 2009, to introduce pharmaceutical companies' approach to implement Risk Management and its proper use for the launch of newly approved anticancer drugs.
MAD-IoT: Memory Anomaly Detection for the Internet of Things

In the Internet of Things (IoT), applications hosted on resource-limited devices interact with the user and the physical world to provide digital connectivity and automation to daily activities, and frequently provide a point of entry into networks. However, many IoT applications are vulnerable to cyber attacks that can put networks, data, and connected devices at risk. Integrity measurement is an active defense technique used to detect malicious modification of software at runtime. While its usefulness has been well-demonstrated, integrity measurement is application-dependent and requires domain knowledge of the targeted software. Currently, adding integrity measurement to a platform requires substantial human effort, and thus application has been limited to usage on widely-deployed software such as the Linux kernel. Due to the diversity of IoT, vendors are unlikely to devote a substantial amount of effort to add integrity measurement systems to their devices. In this paper we introduce MAD- IOT (Memory Anomaly Detection for the Internet of Things), an integrity measurement framework for IoT. In order to provide low-cost integrity measurement agents and software anomaly detection for IoT platforms, MAD-IOT uses a process called IMAGE: Integrity Measurement Agent GEneration. The IMAGE process uses machine learning to automatically generate integrity measurement agents for arbitrary IoT devices. We demonstrated MAD-IOT and IMAGE on a proof-of-concept testbed and evaluated its performance with supervised and unsupervised machine learning models. Our results indicate that IMAGE is highly effective in recognizing known forms of misbehavior on IoT app operations, and very promising in identifying zero-day attacks. Finally, MAD-IOT introduces minimal overhead, making it feasible to implement on systems with very limited resources.
Climate-tracking species are not invasive

Applying an invasive framework to native species that are shifting their ranges in response to climate change adopts an adversarial, local and static paradigm that is often at odds with protecting global biodiversity.
Brain Sex Differences

Once thought of as narrowly limited to reproduction, sex differences in the brain are now emerging as fundamental to a wide swath of neural functioning. Elucidating the cellular mechanisms of how sex differences are established during development provides novel insights into the brain of both sexes. Critical variables include cell death and cell survival pathways, neuroimmune and inflammatory mediators, endocannabinoids, and epigenetics. Gender biases in the risk of neuropsychiatric and neurodegenerative disorders highlight the intrinsic value of elucidating the biological origins of sex differences in the brain.
Responding to the Covid-19 pandemic at a university counseling center: administrative actions, client retention, and psychotherapy outcome

In this article, we examine how Counseling and Psychological Services (CAPS) at a large private university in the western United States addressed the abrupt suspension of in-person mental health se...
Acute Intestinal Ischemia in a Patient with COVID-19 Infection

The World Health Organization has declared novel coronavirus disease 2019 (COVID-19) a global public health emergency. Although respiratory symptoms predominate in COVID-19, thrombosis can occur in patients with COVID-19. This paper reports a case of an 82-year-old female with a prior medical history of hypertension, diabetes presenting with fever and cough, and was diagnosed with COVID-19. The patient subsequently developed progressively worsening of abdominal distention, tenderness, and underwent emergent laparotomy. She was found to have a gangrenous colon. This case adds to the limited literature regarding the extrapulmonary complications of COVID-19. (Korean J Gastroenterol 2020;76:164-166)
Chemical Activation of Water Molecule by Collision with Spin–Orbit-State-Selected Vanadium Cation: Quantum-Electronic-State Control of Chemical Reactivity

We have obtained absolute integral cross sections (σ's) for the reactions of spin-orbit-state-selected vanadium cations, V+[a5DJ(J = 0, 2), a5FJ(J = 1, 2), and a3FJ(J = 2, 3)], with a water molecule (H2O) in the center-of-mass collision energy range Ecm = 0.1-10.0 eV. On the basis of these state-selected σ curves (σ versus Ecm plots) observed, three reaction product channels, VO+ + H2, VH+ + OH, and VOH+ + H, from the V+ + H2O reaction are unambiguously identified. Contrary to the previous guided ion beam study of the V+(a5DJ) + D2O reaction, we have observed the formation of the VO+ + H2 channel from the V+(a5DJ) + H2O ground reactant state at low Ecm's (<3.0 eV). No spin-orbit J-state dependences for the σ curves of individual electronic states are discernible, indicating that spin-orbit interactions are weak with little effect on chemical reactivity of the titled reaction. For the three product channels identified, the triplet σ(a3FJ) values are overwhelmingly higher than the quintet σ(a5DJ) and σ(a5FJ) values, showing that the reaction is governed by a "weak quintet-triplet spin crossing" mechanism, favoring the conservation of total electron spins. The σ curves for exothermic product channels are found to exhibit a rapid decreasing profile as Ecm is increased, an observation consistent with the prediction of the charge-dipole and induced-dipole orbiting model. This experiment shows that the V+ + H2O reaction can be controlled effectively to produce predominantly the VO+ + H2 channel via the V+(a3FJ) + H2O reaction at low Ecm's (≤0.1 eV) and that the ion-molecule reaction dynamics can be altered readily by selecting the electronic state of V+ cation. On the basis of the measured Ecm thresholds for the σ(a5DJ, a5FJ, and a3FJ: VH+) and σ(a5DJ, a5FJ, and a3FJ: VOH+) curves, we have deduced upper bound values of 2.6 ± 0.2 and 4.3 ± 0.3 eV for the 0 K bond dissociation energies, D0(V+-H) and D0(V+-OH), respectively. After correcting for the kinetic energy distribution resulting from the Doppler broadening effect of the H2O molecule, we obtain D0(V+-H) = 2.2 ± 0.2 eV and D0(V+-OH) = 4.0 ± 0.3 eV, which are in agreement with D0 determinations obtained by σ curve simulations.
Daily Associations Among Alcohol Intoxication, Partner Familiarity, Participant Effortful Control, Urgency, and PrEP Uptake on Sexual Behavior in Men Who Have Sex with Men

The purpose of this study was to examine the effects of alcohol intoxication and its interaction with contextual or situation (partner familiarity) and individual differences variables (effortful control, urgency, and whether taking pre-exposure prophylaxis (PrEP) medication) on sexual behaviors in men who have sex with men (MSM), a subgroup for whom HIV continues to be a major public health problem in the U.S. The participants were 236 men recruited from two northeastern U.S. cities and aged 21–50 years, M = 27.8). These men participated in a 6-week (two 3-week sampling bursts) experience sampling method (ESM) study. The ESM data were collected via use of software installed on the participant’s own or study-provided mobile phone. Individual differences variables were measured by participants’ completing questionnaires measuring effortful control and urgency, and the participant’s self-report of whether he was currently taking PrEP. The ESM data pertained to sexual behavior as well as situation variables of familiarity of relevant sexual partners and number of standard alcohol drinks consumed. The results generally were consistent with hypotheses, as alcohol intoxication showed a curvilinear relation to the occurrence of condomless anal intercourse. Furthermore, the likelihood of occurrence of condomless anal sex increased with increased familiarity of the sexual partner. Similarly, taking PrEP increased the likelihood of occurrence of condomless anal sex. At the same time, alcohol’s effects were moderated by all three individual differences variables as expected, but the prediction that partner familiarity would moderate alcohol’s effects on the occurrence of condomless sex was not supported. Clinical implications of the findings center on the application of the data to HIV prevention programs toward inclusion of more empirically supported, nuanced information on the relation between acute alcohol intoxication and sexual behavior. Directions for further research address the need for additional testing and refinement of a person × situation approach to alcohol and sexual behavior. Furthermore, it is argued that it is important to refine further the concept of sexual risk in the context of taking PrEP and to conduct more detailed, multivariate studies of the relation between taking PrEP and patterns of sexual behavior.
Parliamentary scrutiny of the quality of legislation in Germany

In Germany, there is no exhaustive institutionalised process of scrutiny for parliament to ensure the quality of laws. Neither the members of parliament nor the parliamentary administration are tas...
Low Doses of Silver Nanoparticles Selectively Induce Lipid Peroxidation and Proteotoxic Stress in Mesenchymal Subtypes of Triple-Negative Breast Cancer

Molecular profiling of tumors shows that triple-negative breast cancer (TNBC) can be stratified into mesenchymal (claudin-low breast cancer; CLBC) and epithelial subtypes (basal-like breast cancer; BLBC). Subtypes differ in underlying genetics and in response to therapeutics. Several reports indicate that therapeutic strategies that induce lipid peroxidation or proteotoxicity may be particularly effective for various cancers with a mesenchymal phenotype such as CLBC, for which no specific treatment regimens exist and outcomes are poor. We hypothesized that silver nanoparticles (AgNPs) can induce proteotoxic stress and cause lipid peroxidation to a greater extent in CLBC than in BLBC. We found that AgNPs were lethal to CLBCs at doses that had little effect on BLBCs and were non-toxic to normal breast epithelial cells. Analysis of mRNA profiles indicated that sensitivity to AgNPs correlated with expression of multiple CLBC-associated genes. There was no correlation between sensitivity to AgNPs and sensitivity to silver cations, uptake of AgNPs, or proliferation rate, indicating that there are other molecular factors driving sensitivity to AgNPs. Mechanistically, we found that the differences in sensitivity of CLBC and BLBC cells to AgNPs were driven by peroxidation of lipids, protein oxidation and aggregation, and subsequent proteotoxic stress and apoptotic signaling, which were induced in AgNP-treated CLBC cells, but not in BLBC cells. This study shows AgNPs are a specific treatment for CLBC and indicates that stratification of TNBC subtypes may lead to improved outcomes for other therapeutics with similar mechanisms of action.
Outcomes of Thoracic Endovascular Aortic Repair in Octogenarians.

ObjectiveThe aim of this study is to compare outcomes between octogenarians and non-octogenarians undergoing thoracic endovascular aortic repair (TEVAR).MethodsUsing the National Inpatient Sample d...
Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience.

Summary Gene Ontology analyses of autism spectrum disorders (ASD) risk genes have repeatedly highlighted synaptic function and transcriptional regulation as key points of convergence. However, these analyses rely on incomplete knowledge of gene function across brain development. Here we leverage Xenopus tropicalis to study in vivo ten genes with the strongest statistical evidence for association with ASD. All genes are expressed in developing telencephalon at time points mapping to human mid-prenatal development, and mutations lead to an increase in the ratio of neural progenitor cells to maturing neurons, supporting previous in silico systems biological findings implicating cortical neurons in ASD vulnerability, but expanding the range of convergent functions to include neurogenesis. Systematic chemical screening identifies that estrogen, via Sonic hedgehog signaling, rescues this convergent phenotype in Xenopus and human models of brain development, suggesting a resilience factor that may mitigate a range of ASD genetic risks.
The Myasthenic Syndromes

This chapter deals with disorders of the neuromuscular junction including myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital disorders of neuromuscular transmission (CDNT). The pathophysiologies of these disorders lie at the presynaptic nerve terminal and the specialized structures located on the postsynaptic skeletal muscle membrane. The myasthenic syndromes are of general interest because an understanding of the pathophysiology at the neuromuscular junction may provide insight into disorders at other neural synapses as, for example, may occur in certain epileptic disorders. In addition, understanding the consequence of specific mutations in the nicotinic acetylcholine receptor (AChR), as occurs in some of the CDNT, may provide insights into the structure-function relationships of the AChR.
Repair and Recombination of DNA Molecules

Every organism has mechanisms for maintaining the integrity of its nucleic acid (i.e., for repairing any damage). Nevertheless, most organisms, including even bacteria and viruses, exhibit some sort of genetic exchange. The two processes may seem antithetical, as recombination, the movement of genetic information from one molecule of nucleic acid to another, implies that the nucleic acid undergoes some kind of structural alteration. However, as is discussed in this chapter, many of the steps involved in completion of the recombination process are the same as those involved in repair, and recombination can be looked on as a process in which tree potential for damage to the nucleic acid is outweighed by the potential benefit to be derived from the new genetic information.
Qualitative and quantitative assessment of the circadian rhythm of cortisol in pregnancy

The effect of pregnancy on the circadian rhythm and diurnal excursion of plasma cortisol and urinary free corticoids was examined in a sequential study during the second and third trimester and 6 to 12 weeks post partum. Hourly blood samples from six subjects and 8-hour urine collections from eight subjects were obtained around the clock. While the circadian rhythm was maintained during gestation, plasma cortisol levels (24-hour mean, nadir, peak, and nadir-peak excursion) increased. The relative excursion of plasma cortisol (expressed as the percentage of deviation from the 24-hour mean) exhibited remarkable blunting compared with postpartum values. This pregnancy-associated blunting of plasma cortisol excursion was indicated by a significant reduction in the: (1) mean peak and nadir excursion, (2) integrated area between the percent deviation curve and the 24-hour mean, and (3) mean slope of the major incremental and decremental segments of the percent deviation curve. The circadian rhythm and diurnal excursion of plasma cortisol were reflected in urinary free corticoid values. Mean 24-hour urinary free corticoid concentrations increased 180% during gestation over nonpregnant levels. Nadir concentrations of urinary free corticoids in pregnancy exceeded peak nonpregnant levels. The gestational rise of metabolically active free cortisol and adrenocorticotropin (ACTH), and the pregnancy-associated blunting of the excursion of plasma cortisol may be explained by an autonomous source of ACTH during gestation.
Tableaux, Path Dissolution, and Decomposable Negation Normal Form for Knowledge Compilation

Decomposable negation normal form (DNNF) was developed primarily for knowledge compilation. Formulas in DNNF are linkless, in negation normal form (NNF), and have the property that atoms are not shared across conjunctions. Full dissolvents are linkless NNF formulas that do not in general have the latter property. However, many of the applications of DNNF can be obtained with full dissolvents. Two additional methods — regular tableaux and semantic factoring — are shown to produce equivalent DNNF. A class of formulae is presented on which earlier DNNF conversion techniques are necessarily exponential; path dissolution and semantic factoring handle these formulae in linear time.
An architecture for fast data movement in the FFP machine

We propose an extension to the architecture of the FFP machine which permits storage management in O(log n) time and arbitrary data rearrangement in O(log2 n) time, assuming messages are transmitted in unit time independent of wire length. This is achieved using a perfect shuffle sorter network with the FFP machine. The cost is only a constant amount of hardware per atomic symbol. We also propose mechanisms for early termination, that is, easy rearrangements may be performed faster than the worst case time. We propose a hierarchical structure to the FFP machine which is compatible with a modification of the perfect shuffle sorter network. This permits local operations to be faster than global operations, and permits the FFP machine to operate as a collection of independent processors when desired. A method for giving the programmer some control of the use of this hierarchy is proposed. The FFP machine selects certain subexpressions of the input string to be processed during each computation step. These subexpressions are effectively isolated from the rest of the input string during the computation. We show how this isolation may be accomplished in the perfect shuffle sorter network without giving unique names to each such subexpression. This architecture permits fast operations, such as the multiplication of two m by m matrices in O(log2 m) time.
ELSI Research Programme of the NHGRI

The Ethical, Legal and Social Implications (ELSI) research programme of the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) is a grant programme that supports research designed to anticipate and address the implications of human genetics and genomics research for individuals, families, communities and society. Programme staff and the researchers the programme supports are involved in the bioethics components of major genomics research projects and in many activities that inform genomics-related research, health and social policies. The programme operates collaboratively with the genomics research community, and in general, the supported research has brought greater depth and strength to the genomics research enterprise. The ELSI programme is a unique experiment in the annals of NIH-funded biomedical research, and initial results indicate that the experiment has been successful. Key concepts: The Ethical, Legal and Social Implications (ELSI) research programme, within the Division of Extramural Research at the National Human Genome Research Institute of the National Institutes of Health, supports research designed to anticipate and address the implications of human genetic and genomic research, technologies and information. The ELSI programme is currently the largest governmental supporter of bioethics research in the world. Most ELSI research is investigator-initiated, but the programme periodically issues requests for applications (RFAs) to solicit research targeted at particular high-priority areas. Neither genomics researchers nor administrators responsible for the oversight of genomics research have controlled the content or direction of ELSI research. The research priorities of the ELSI programme have evolved and span a range of issues relating to the implications of genomics for individuals, families, communities and the broader society. ELSI research aims to be anticipatory by encouraging researchers to identify issues likely to be raised by advances in genetics and genomics research before they arise. ELSI research involves researchers from a wide range of disciplines and is often highly transdisciplinary. The involvement of ELSI programme staff and ELSI researchers in major genomics research projects makes it possible to marshal the findings of relevant ELSI studies directly to inform the design and conduct of genomics research. ELSI research has had a considerable impact on both health care and broader social policies. Keywords: ethics; bioethics; policy; genomics; ELSI
Estimation of distributed hybrid systems Using particle filtering methods

Networked embedded systems are composed of a large number of components that interact with the physical world via a set of sensors and actuators, have their own computational capabilities, and communicate with each other via a wired or wireless network. Such systems are best modeled by distributed hybrid systems that capture the interaction between the physical and computational components. Monitoring and diagnosis of any dynamical system depend crucially on the ability to estimate the system state given the observations. Estimation for distributed hybrid systems is particularly challenging because it requires keeping track of multiple models and the transitions between them. This paper presents a particle filtering based estimation algorithm for a class of distributed hybrid systems. The hybrid estimation methodology is demonstrated on a cryogenic propulsion system.
Monoclonal Antibodies Reveal Cell-Type-Specific Antigens in the Sexually Dimorphic Olfactory System of Manduca sexta. I. Generation of Monoclonal Antibodies and Partial Characterization of the Antigens

The olfactory system of the moth Manduca sexta is sexually dimorphic. Male moths possess a male-specific olfactory "subsystem," comprising olfactory receptor cells (ORCs) and CNS neurons and synaptic areas associated with the detection of female sex pheromones, in addition to elements common to males and females. In order to explore the molecular differences between cells that subserve the sexual dimorphism and odor-specificity of components of the olfactory system, we generated monoclonal antibodies (Mabs) against tissue of the olfactory system of the moth. In 2 fusions, we screened 1105 hybridoma lines and obtained 272 lines that secreted antibodies against Manduca nervous tissue, as assayed immunocytochemically on sections of the primary olfactory center (the antennal lobe) in the brain of Manduca. We describe here 3 classes of Mabs exemplifying the several cell-type-specific antibodies obtained through the screening procedure. Seven hybridoma lines secrete antibodies that specifically recognize cell bodies, axons, and initial segments of dendrites of many or all ORCs of both males and females (classified as olfactory-specific antibodies, OSAs). Electron-microscopic studies of 2 of the Mabs in this class showed that they recognize antigens associated with the cell membrane and that the immunoreactive ORC axons are bundled together in fascicles in the antennal nerve. On immunoblots, one of the OSA Mabs recognizes 3 distinct protein bands of apparent Mrs 42,000, 59,000, and 66,000 Da. When tissue samples enriched in either receptor cell bodies, dendrites, and initial segments of axons or in distal segments of axons and their terminals and synapses were extracted separately, different patterns of bands were detected--42,000 and 59,000 Da bands from cell bodies and initial segments of axons and dendrites, and 42,000 and 66,000 Da bands from distal segments of axons and their terminals--suggesting that the 59,000 Da protein is modified to the 66,000 Da protein during axonal transport. The second Mab we describe here, the male olfactory-specific antibody (MOSA), selectively recognizes the sexually dimorphic ORCs that are present only in males. The antigen recognized by this antibody is found in cell bodies, dendrites, axons, and axon terminals. By electron-microscopic immunocytochemistry, the MOSA immunoreactivity is found in the cytoplasm and appears not to be associated with particular subcellular organelles. This antibody demonstrates that male-specific ORCs are molecularly distinct from other types of ORCs.(ABSTRACT TRUNCATED AT 400 WORDS)
Noise-supported travelling waves in sub-excitable media

The detection of weak signals of nonlinear dynamical systems in noisy environments may improve with increasing noise, reaching an optimal level before the signal is overwhelmed by the noise. This phenomenon, known as stochastic resonance1,2, has been characterized in electronic3, laser4, magnetoelastic5, physical6 and chemical7 systems. Studies of stochastic resonance and noise effects in biological8,9 and excitable dynamical systems10,11,12,13 have attracted particular interest, because of the possibility of noise-supported signal transmission in neuronal tissue and other excitable biological media. Here we report the positive influence of noise on wave propagation in a photosensitive Belousov–Zhabotinsky14,15,16,17 reaction. The chemical medium, which is sub-excitable and unable to support sustained wave propagation, is illuminated with light that is spatially partitioned into an array of cells in which the intensity is randomly varied. Wave propagation is enhanced with increasing noise amplitude, and sustained propagation is achieved at an optimal level. Above this level, only fragmented waves are observed.
The effect of calcium ion channel blockers on sperm fertilization potential

Objective To evaluate the effects of calcium ion (Ca 2+ ) channel blockers on male fertility potential. Design A case comparison of the surface expression of mannose-ligand receptors on motile spermatozoa from 10 known fertile males and from 10 normospermic men taking Ca 2+ channel blockers who were seeking infertility treatment. Examination of the effects of in vitro exposure of sperm from fertile donors (n = 14) to antihypertensive medications. Setting Patients from a successful university hospital-based IVF-assisted reproductive technology program and from a male urology private practice. Interventions Prescription of alternate hypotensive medications for four male patients; cholesterol loading and unloading in vitro of fertile donor sperm. Main Outcome Measures Motile sperm were tested for their ability to bind fluorescein isothiocyanate-labeled, mannosylated bovine serum albumin as an index of the surface expression of mannose-ligand receptors associated with fertility potential. Acrosome status was simultaneously evaluated by fluorescence microscopy with rhodamine-labeled Pisum sativum lectin. Sperm were assayed before and after an 18-hour or 3-day incubation under capacitating conditions in vitro. Results Motile spermatozoa of normospermic men taking calcium antagonists for hypertension control do not express head-directed mannose-ligand receptors at high frequency, nor do they undergo spontaneous acrosome loss. Unexpectedly, mannose-ligand receptor translocation from the subplasmalemmal space over the acrosome to the sperm surface and aggregation over the equatorial-postacrosomal regions occurred in acrosome-intact sperm. This differs from fertile controls in whom receptor translocation to the equatorial-postacrosomal segment is coupled with the acrosome reaction (AR). Discontinuation of calcium antagonists results in complete recovery of parameters associated with sperm fertilizing potential: time-dependent increases in the percentages of spermatozoa exhibiting surface mannose-ligand binding and spontaneous ARs in vitro. The effects of in vivo administration of calcium antagonists is mimicked in control fertile donor sperm by inclusion of a Ca 2+ channel blocker in the media employed during capacitating incubations. Conclusions Therapeutic administrations of calcium antagonists for hypertension control cause reversible male infertility associated with an IVF failure. A mechanism of inhibition of sperm fertilizing potential through insertion of lipophilic calcium ion antagonists into the lipid bilayer of the sperm plasma membrane is consistent with our in vitro studies.
The attachment to human buccal epithelial cells by Candida albicans: an in vitro kinetic study using concanavalin A.

The early in vitro kinetics of Candida albicans attachment to human buccal epithelial cells was studied with the aid of an adhesion assay and solutions of concanavalin A (Con A), a lectin which is capable of inhibiting yeast adhesion. Various saccharides and putative receptor analogues were also tested. Solutions of each single reagent were added to tubes containing aliquots of mucosal cells and germinated yeasts at the beginning of a 1-hour incubation period (time O) or at 10 minute intervals during the assay. The number of yeasts attached to 200 mucosal cells was subsequently determined microscopically. Yeast adhesion remained constant following addition of phosphate-buffered saline (PBS) at time 0 or at any time thereafter. However, addition of Con A at 0, 10 or 20 minutes of incubation decreased adhesion significantly to 38%, 45% and 63% of control values. This inhibitory effect dwindled as time of incubation prior to lectin addition increased and Con A could not inhibit adhesion significantly after twenty minutes. Results obtained with Con A using live germinated yeasts were similar to those obtained with formalin-killed C. albicans. The other reagents tested failed to decrease adhesion significantly. These included the putative receptor analogues fibronectin, N-acetyl-d-glucosamine and d-galactose, and several non-specific saccharides such as α-d-methylglucopyranoside, d-ribose and d-xylose. It is suggested that in vitro attachment to human mucosal cells by C. albicans is inhibitable up to a defined point in time by a lectin with affinity for mannosecontaining surface moieties, but becomes non-reversible thereafter. This experimentally-observed irreversibility is independent of yeast cell viability.
Interpretation of Graphs that Compare the Distribution Functions of Estimators

In this paper I examine graphical comparisons of one-dimensional (or marginal) distribution functions of alternative estimators. It is shown that areas under the c.d.f. (cumulative distribution function) curve can be given a decision-theoretic interpretation as risk under a bounded absolute-error loss function. I also show that by a simple rescaling of the graph's axes, graphical areas are created which can be interpreted as risk under bounded squared-error loss. The bounded loss functions are applied to compare graphically and numerically the risk of exact distributions of the limited-information maximum likelihood and two-stage least-squares estimators in a simultaneous equations model.