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Summary Characterization of I37R, a mutation located in the lasso motif of the CFTR chloride channel, was conducted by theratyping several CFTR modulators from both potentiator and corrector classes. Intestinal current measurements in rectal biopsies, forskolin-induced swelling (FIS) in intestinal organoids, and short circuit current measurements in organoid-derived monolayers from an individual with I37R/F508del CFTR genotype demonstrated that the I37R-CFTR results in a residual function defect amenable to treatment with potentiators and type III, but not type I, correctors. Molecular dynamics of I37R using an extended model of the phosphorylated, ATP-bound human CFTR identified an altered lasso motif conformation which results in an unfavorable strengthening of the interactions between the lasso motif, the regulatory (R) domain, and the transmembrane domain 2 (TMD2). Structural and functional characterization of the I37R-CFTR mutation increases understanding of CFTR channel regulation and provides a potential pathway to expand drug access to CF patients with ultra-rare genotypes., Graphical abstract, Highlights • I37R-CFTR localizes to the cell surface and results in a residual function defect • I37R-CFTR breaks a conserved salt bridge perturbing the lasso motif • I37R-CFTR strengthens lasso interaction with the R domain, impacting channel gating • I37R-CFTR is responsive to potentiators (GLPG1837) and class III correctors (VX-445), Pharmacology; Biochemistry; Structural biology

Highlights • GILT is upregulated in chemoresistant LSC-enriched CD34+ progenitor cells. • Inhibition of GILT in AML cells sensitized them to Ara-C treatment through ROS-mediated mitochondrial damage and apoptosis. • PI3K/Akt/NRF2 pathway inhibition is critical for the intracellular oxidative state in GILT-suppression AML cells after Ara-C treatment. • GILT expression is related to a poor prognosis in AML patients., The persistence of leukemia stem cells (LSCs) is one of the leading causes of chemoresistance in acute myeloid leukemia (AML). To explore the factors important in LSC-mediated resistance, we use mass spectrometry to screen the factors related to LSC chemoresistance and defined IFN-γ-inducible lysosomal thiol reductase (GILT) as a candidate. We found that the GILT expression was upregulated in chemoresistant CD34+ AML cells. Loss of function studies demonstrated that silencing of GILT in AML cells sensitized them to Ara-C treatment both in vitro and in vivo. Further mechanistic findings revealed that the ROS-mediated mitochondrial damage plays a pivotal role in inducing apoptosis of GILT-inhibited AML cells after Ara-C treatment. The inactivation of PI3K/Akt/ nuclear factor erythroid 2-related factor 2 (NRF2) pathway, causing reduced generation of antioxidants such as SOD2 and leading to a shifted ratio of GSH/GSSG to the oxidized form, contributed to the over-physiological oxidative status in the absence of GILT. The prognostic value of GILT was also validated in AML patients. Taken together, our work demonstrated that the inhibition of GILT increases AML chemo-sensitivity through elevating ROS level and induce oxidative mitochondrial damage-mediated apoptosis, and inhibition of the PI3K/Akt/NRF2 pathway enhances the intracellular oxidative state by disrupting redox homeostasis, providing a potentially effective way to overcome chemoresistance of AML., Graphical abstract GILT inhibition overcomes chemoresistance in AML Left panel. Despite that Ara-C stimulates ROS generation and causes oxidative stress, chemoresistance can still develop as a result of compensatory elevation of antioxidants that detoxify the harmful oxidants. Activation of P13K/Akt/NRF2 pathwaypromotes expressionofantioxidants. Right panel. GILT knockdown facilitates disturbance of redox homeostasis of AML cell by (i) enhancing Ara-C-stimulated ROS over-production, (ii) reducing antioxidant level which is associated with inactivation of the P13K/Akt/NRF2 axis. The resulting severe oxidative stress leads to mitochondrial damage and apoptosis. Image, graphical abstract

Walking is a common activity among older adults. Fallers were discovered to have a higher propensity to conscious motor processing (reinvestment) than age-matched non-fallers, leading to movement disruption, possibly by constraining or interfering with automatic motor control mechanisms. However, gait rehabilitation programs by implicit motor learning methodologies may ameliorate reinvestment propensity while improving gait ability in older adults. One hundred and five older adults, with moderate to high risk of falling, will be recruited from different community centres in Hong Kong to investigate the effect of single-task, dual-task and analogy training (implicit motor learning methodologies) on walking during rehabilitation in the context of reinvestment propensity, balance, walking ability and fear of falling. Participants will be randomly allocated and received 12 training sessions in either a Single-task Walking Group (STWG), a Dual-task Walking Group (DTWG) or an Analogy Walking Group (AGWG). Reinvestment propensity, walking ability, balance and fear of falling will be assessed by the Chinese version Movement Specific Reinvestment Scale (MSRS-C), 10-meter Walk Test, Tinetti Balance Assessment Tool, Timed ‘Up & Go’ Test (TU&G), Berg Balance Scale (BBS) and 13-item Falls Efficacy Scale (FES-13), respectively at baseline before training (T0), just after completion of all training sessions (T1), and 6 months after completion of all training sessions (T2). Participants' number of falls between T1 and T2 will also be recorded. The results could establish a solid foundation for further development and implementation of a novel and effective gait rehabilitation program in fall prevention for older adults at risk of falling. Keywords: Single-task training, Dual-task training, Analogy training, Gait rehabilitation, Older adults

Falls in older adults are a major global public health concern. Group exercise could mitigate fall risk but the traditional land-based group exercise may not be always suitable for older adults at risk of falling, especially for those with musculoskeletal problems. Ai Chi aquatic exercise program could provide a safe and low-impact exercise training for older adults. However, the feasibility and efficacy of the program has not been well-investigated. The objective of this study is to investigate the feasibility and efficacy of the Ai Chi aquatic exercise program, compared to the land-based exercise program for older adults with moderate to high risk of falling. Forty community-dwelling older adults aged 65 or above with moderate to high fall risk will be recruited. They will be randomly allocated in the Ai Chi Aquatic Exercise Group (intervention) or the Land-based Exercise Group (active control) receiving 16 sessions (8 weeks) of specific exercise training. Feasibility of both exercise groups will be examined by recruitment, adherence, retention, feedback, subjective exercise experiences and satisfaction. Preliminary efficacy will be determined by whether physical and psychological fall risk factors could be mitigated. Physical fall risk assessment will include tests for flexibility, muscle strength, gait and balance. Psychological fall risk will be evaluated by preliminary cognitive function, anxiety level, level of depression and fear of falling. The results could establish a solid foundation for worldwide development of a feasible, safe and effective Ai Chi aquatic exercise program for prevention of falls in older adults with risk of falling. Keywords: Fall prevention, Older adults, Ai chi aquatic exercise, Land-based exercise, Feasibility, Efficacy

Background Post-thrombotic syndrome is a common complication of iliofemoral deep venous thrombosis (IFDVT). Existing evidence and National Institute for Health and Care Excellence guidelines suggest that this can be reduced by prompt thrombolytic therapy or thrombectomy. We aimed to evaluate the characteristics of IFDVT patients and to identify whether patients are being offered the recommended treatment pathway. Methods A multicenter cross-sectional study was conducted across eight hospital sites in the North West London region, of which two were hub hospitals in their local vascular service networks. Patients with proximal DVT were identified using International Classification of Diseases, Tenth Revision coding during a 1-year period. Data on demographics, diagnostic methods used, interventions, and referrals were extracted from electronic and paper medical records. Results During the study period, 132 patients with IFDVT were identified (mean age, 59.4 years; 55% female); 75% of these patients had an IFDVT. In this cohort, the biggest predisposing factors were previous DVT (n = 35), malignant disease (n = 35), and immobility (n = 20). In total, 104 patients were administered anticoagulation, and 88 of these patients received anticoagulation within 24 hours. The cases of 45 patients were either discussed with or promptly referred to a vascular service, after which 20 patients were treated solely with anticoagulation, whereas 20 patients received thrombolysis of varying methods. Conclusions A significant proportion (56%) of symptomatic IFDVT patients are not being appropriately referred to or discussed with vascular services. Of these, 43% would have been eligible for consideration of early thrombus removal. Adherence to the National Institute for Health and Care Excellence guidelines could be improved by increasing awareness among emergency department colleagues.

The Alice instrument on NASA's New Horizons spacecraft observed an ultraviolet solar occultation by Pluto's atmosphere on 2015 July 14. The transmission vs. altitude was sensitive to the presence of N_2, CH_4, C_2H_2, C_2H_4, C_2H_6, and haze. We derived line-of-sight abundances and local number densities for the 5 molecular species, and line-of-sight optical depth and extinction coefficients for the haze. We found the following major conclusions: (1) We confirmed temperatures in Pluto's upper atmosphere that were colder than expected before the New Horizons flyby, with upper atmospheric temperatures near 65–68 K. The inferred enhanced Jeans escape rates were (3–7) × 10^(22) N_2 s^(−1) and (4–8) × 10^(25) CH_4 s^(−1) at the exobase (at a radius of ∼ 2900 km, or an altitude of ∼1710 km). (2) We measured CH_4 abundances from 80 to 1200 km above the surface. A joint analysis of the Alice CH_4 and Alice and REX N_2 measurements implied a very stable lower atmosphere with a small eddy diffusion coefficient, most likely between 550 and 4000 cm^2 s^(−1). Such a small eddy diffusion coefficient placed the homopause within 12 km of the surface, giving Pluto a small planetary boundary layer. The inferred CH_4 surface mixing ratio was ∼ 0.28–0.35%. (3) The abundance profiles of the “C_2H_x hydrocarbons” (C_2H_2, C_2H_4, C_2H_6) were not simply exponential with altitude. We detected local maxima in line-of-sight abundance near 410 km altitude for C_2H_4, near 320 km for C_2H_2, and an inflection point or the suggestion of a local maximum at 260 km for C_2H_6. We also detected local minima near 200 km altitude for C_2H_4, near 170 km for C_2H_2, and an inflection point or minimum near 170–200 km for C_2H_6. These compared favorably with models for hydrocarbon production near 300–400 km and haze condensation near 200 km, especially for C_2H_2 and C_2H_4 (Wong et al., 2017). (4) We found haze that had an extinction coefficient approximately proportional to N_2 density.

Interpretation of CT or MR imaging examinations performed on patients with a history of middle ear, mastoid, or neurotologic surgery can be challenging. This is greatly simplified by knowing the surgical procedures used. Knowledge of the expected normal versus abnormal postoperative appearance is the key to recognizing complications or recurrent disease. This chapter initially discusses the surgical approaches to the middle ear and mastoid (transcanal, retroauricular, endaural) and the procedures facilitated by these (meatoplasty, canaloplasty, myringoplasty, tympanoplasty, ossiculoplasty, stapedectomy, mastoidectomy). Imaging findings indicative of recurrent disease are then discussed to include MR imaging for the detection of cholesteatoma. The chapter concludes with a discussion of surgical approaches to the internal auditory canal and otic capsule (retrosigmoid, middle cranial fossa, translabyrinthine, transmastoid) for the management of tumors and superior semicircular canal dehiscence.

Organic nanoparticle-based (ONP) gene therapy is a potential strategy to cure human cancer. However, there are still many practical barriers before the promising results from in vitro and preclinical studies can be translated to clinical success. We discuss the reasons behind the hesitant uptake by the clinic.

The present study examined the genetic and environmental etiology of the connection between speech and word reading in Chinese. A total of 371 pairs of Chinese twins (278 pairs of monozygotic twins and 93 pairs of same-sex dizygotic twins) were tested on speech discrimination and production, phonological skills, semantic skills, and Chinese word reading at the mean age 7.4 years. Results of univariate genetic analyses showed moderate genetic influences on speech, semantic skills, and Chinese word reading, while moderate shared environmental influences on phonological skills. The genetic correlations among all the variables were significant. Results of testing several models on the link between speech and word reading supported a common genetic factor underlying speech, phonological skills, semantic skills, and word reading in Chinese. The present findings suggest that around 50% to 60% of individual differences of speech, semantic skills, and word reading in Chinese are due to genetic factors. Individual differences of phonological skills appear to be relatively less heritable than those in English. This may be partly due to the fact that the Chinese script does not map directly on any segmental phonological information. A single common genetic etiology for speech, phonological skills, semantic skills, and word reading suggests that development of these skills is highly connected.

The New Horizons flyby of Pluto confirmed the existence of hazes in its atmosphere. Observations of a large high- to low- phase brightness ratio, combined with the blue color of the haze, suggest that the haze particles are fractal aggregates, analogous to the photochemical hazes on Titan. Therefore, studying the Pluto hazes can shed light on the similarities and differences between the Pluto and Titan atmospheres. We model the haze distribution using the Community Aerosol and Radiation Model for Atmospheres assuming that the distribution is shaped by sedimentation and coagulation of particles originating from photochemistry. Hazes composed of both purely spherical and purely fractal aggregate particles are considered. Agreement between model results and occultation observations is obtained with aggregate particles when the downward flux of photochemical products is equal to the column-integrated methane destruction rate ~1.2 $\times$ 10$^{-14}$ g cm$^{-2}$ s$^{-1}$, while for spherical particles the mass flux must be 2-3 times greater. This flux is nearly identical to the haze production flux of Titan previously obtained by comparing microphysical model results to Cassini observations. The aggregate particle radius is sensitive to particle charging, and a particle charge to radius ratio of 30 e-/{\mu}m is necessary to produce ~0.1-0.2 {\mu}m aggregates near Pluto's surface, in accordance with forward scattering measurements. Such a particle charge to radius ratio is 2-4 times higher than those previously obtained for Titan. Hazes composed of spheres with the same particle charge to radius ratio have particles that are 4 times smaller. These results further suggest that the haze particles are fractal aggregates. We also consider the effect of condensation of HCN, and C$_{2}$-hydrocarbons on the haze particles, which may play an important role in shaping their distributions., Comment: 30 pages, 6 figures. Accepted for publication in Icarus

SummaryPhytochromes are red/far-red light receptors that function in photomorphogenesis of plants. Photoisomerization of phytochrome by red light leads to its translocation to the nucleus, where it regulates gene expression. We examined whether phytochrome is phosphorylated in response to light, and we report that phytochrome B (phyB)’s N terminus contains a region with a number of phosphoserines, threonines, and tyrosines. The light-dependent phosphorylation of tyrosine 104 (Y104) appears to play a negative role in phyB’s activity, because a phosphomimic mutant, phyBY104E, is unable to complement any phyB-related phenotype, is defective in binding to its signaling partner PIF3, and fails to form stable nuclear bodies even though it retains normal photochemistry in vitro. In contrast, plants stably expressing a nonphosphorylatable mutant, phyBY104F, are hypersensitive to light. The proper response to changes in the light environment is crucial for plant survival, and our study brings tyrosine phosphorylation to the forefront of light-signaling mechanisms.

Cerium oxide nanoparticles, nanoceria, are inorganic antioxidants that have catalytic activities which mimic those of the neuroprotective enzymes superoxide dismutase and catalase. We have previously shown that nanoceria preserve retinal morphology and prevent loss of retinal function in a rat light damage model. In this study, the homozygous tubby mutant mouse, which exhibits inherited early progressive cochlear and retinal degeneration, was used as a model to test the ability of nanoceria to slow the progression of retinal degeneration. Tubby mice were injected systemically, intracardially, with 20 μl of 1 mM nanoceria in saline, at postnatal day 10 and subsequently at P20 and P30 whereas saline injected and uninjected wild type (or heterozygous tubby) served as injected and uninjected controls, respectively. Assays for retinal function, morphology and signaling pathway gene expression were performed on P34 mice. Our data demonstrate that nanoceria protect the retina by decreasing Reactive Oxygen Species (ROS), up-regulating the expression of neuroprotection-associated genes; down-regulating apoptosis signaling pathways and/or up-regulating survival signaling pathways to slow photoreceptor degeneration. These data suggest that nanoceria have significant potential as global agents for therapeutic treatment of inherited retinal degeneration and most types of ocular diseases.

In the presence of specialized proteins or peptides, a biological membrane can spontaneously restructure itself to allow communication between the intracellular and the extracellular sides. Examples of these proteins include cell-penetrating peptides and antimicrobial peptides (AMPs), which interact with cell membranes in complex ways. We briefly review cell-penetrating peptides and AMPs, and describe in detail how recombinant AMPs are made and their activity evaluated, using α-defensins as a specific example. We also review X-ray scattering methods used in studying peptide-membrane interactions, focusing on the procedures for small-angle X-ray scattering experiments on peptide-membrane interactions at realistic solution conditions, using both laboratory and synchrotron sources.

In fish, growth hormone (GH) affects many functions, including somatic growth, energy metabolism, reproduction, feeding, osmoregulation and immune functions. GH release and synthesis are controlled by neuroendocrine factors from the brain and peripheral tissues. Hypothalamic regulators influence the expression of one another, forming an interacting network in GH regulation. GH release is inhibited tonically by somatostatin with insulin‐like growth factor as a major feedback regulator; however, the actual amount of GH released reflects the balance of total inhibitory and stimulatory influences. Sex steroids and nutritional status also modulate the expression and pituitary actions of hypothalamic factors. Intrapituitary regulators, including GH, gonadotropin and inhibin/activin, provide autocrine/paracrine control over GH synthesis and secretion. At the somatotrope level, receptor expression for a multitude of neuroendocrine factors can integrate the regulatory signals from various regulators. The distinct and yet overlapping signaling cascades utilized by different regulators allow for ligand‐ and function‐specificity for GH regulation.

Publisher Summary The chapter describes innovative FRP-steel-concrete hybrid columns. Hybrid FRP-concrete-steel double-skin tubular columns are a new form of hybrid columns. The column consists of an outer tube made of fiber-reinforced polymer (FRP) and an inner tube made of steel, with the space between filled with concrete. In this new hybrid column, three constituent materials are optimally combined to achieve several advantages not available with existing columns. The chapter explains the rationale for the new column form together with its expected advantages. Results from a series of stub column tests are presented and discussed to confirm some of these expected advantages. A series of four-point bending tests is also presented to understand the flexural behavior of such hybrid columns. A series of stub column tests to confirm some of the expected advantages are conducted, and the results are presented and discussed in the chapter. The test results confirms that the concrete in the new column is very effectively confined, leading to a very ductile response. The inner void in the double-skin column is found to have almost no effect on the effectiveness of the confinement provided by the FRP tube.

Fertilization is the union of a single sperm and an egg, an event that results in a diploid embryo. Animals use many mechanisms to achieve this ratio; the most prevalent involves physically blocking the fusion of subsequent sperm. Selective pressures to maintain monospermy have resulted in an elaboration of diverse egg and sperm structures. The processes employed for monospermy are as diverse as the animals that result from this process. Yet, the fundamental molecular requirements for successful monospermic fertilization are similar, implying that animals may have a common ancestral block to polyspermy. Here, we explore this hypothesis, reviewing biochemical, molecular, and genetic discoveries that lend support to a common ancestral mechanism. We also consider the evolution of alternative or radical techniques, including physiological polyspermy, with respect to our ability to describe a parsimonious guide to fertilization.

Publisher Summary This chapter focuses on the shear transfer mechanism of pre-stressed concrete encased steel (PCES) beam—a hybrid structural member that has not been thoroughly studied. Although a PCES beam is a hybrid beam comprising the features of pre-stressed concrete beams and structural steel beams, it is doubtful that either Diagonal Compression Field Theory or Diagonal Tension Field Action mechanism or both can be used to model the shear resistance of the hybrid beam. In this chapter, the results of shear tests on 6 PCES with bonded tendons are examined. The purpose of the test is to elucidate the shear performance of PCES with bonded tendons under monotonic loading. Evaluation and comparison of test results of PCES with the effect of various arrangements are made, such as number of stirrups, shear span depth ratio, and eccentricity of I beam. It is found that the contribution of concrete section to the overall shear resistance is significant, particularly at the onset of diagonal shear cracks. This chapter also demonstrates that the new pre-stressed concrete encased steel (PCES) beam system has a good potential for practical applications because it exhibits high stiffness and strength at service and ultimate states respectively, and considerable dependable ductility in the post-peak performance.

Publisher Summary This chapter proposes a 2-D mesoscopic thermoelastic damage (MTED) model used to study the thermal stress field and associated fracture in a cement-based composite with multiple circular inclusions at high temperatures. The cement-based composite is made of two-phase materials, each of which at mesoscale is heterogeneous. The interface bonding between the matrix and the inclusion is assumed to be perfect. A statistical Weibull distribution is used to describe the heterogeneity of the phase material using a homogeneity index. The mechanical properties are randomly allocated to each representative volume element (RVE) to account for the inherent variability in the phase material, using the Monte–Carlo method. The coefficient of thermal expansion (CTE) and mechanical properties of the matrix and inclusions are considered to be independent of temperature variations. When the CTE of inclusion is larger than that of the matrix, the inclusion and the matrix are subjected to statistically hydrostatic compression and a combination of compression and tension, respectively. A high stress region is induced at the interface between the matrix and the inclusion by the thermal mismatch, and in the area between any two-neighborhood inclusions with the shortest distance apart.

Publisher Summary This chapter develops the state space of base shear-torque for estimation of the seismic performance particularly the torsional effects of the RC asymmetric structures based on the experimental results and the assumption of the bi-linear force-displacement relationship. The base shear-torque (BST) surfaces of the asymmetric model structures are founded based on the assumption of idealized force-displacement relationship, while only single-directional ground excitation is considered for convenience of comparison. In most experimental cases, there is no pure torsional damage observed from the responses of the base shear-torque. Although the BST surface established on the assumption of idealized force-displacement relationship can be roughly used to estimate the seismic performance of asymmetric systems, it brings significant error on the prediction of the nonlinear response when the studied structure suffered strong earthquakes. Therefore, based on the assumption of the bi-linear force-displacement relationship and the displacement-based method to determine the stiffness, the state space signifying the base shear-torque relationship is developed to describe the entire seismic capacity of the asymmetric systems. It shows high consistency with the experimental results.

Publisher Summary This chapter discusses a pseudodynamic testing system developed with the incorporation of the substructure technique. Pseudodynamic test method is an experimental technique for simulating the time-history response of structural members. It combines the realism of shaking table tests with the economy and convenience of quasistatic testing. The pseudodynamic system has been implemented to study the seismic response of a transfer plate in 18-storey high-rise building. Structural system comprises a transfer plate at the first floor with evenly spaced columns below, and shear walls above the transfer. A test specimen in 1/4-scale was used to model the ground floor, transfer plate, and the second floor. All the upper storeys were simulated numerically. Pseudodynamic tests were conducted using three types of time-history records. When subject to an El-Centro earthquake record with maximum acceleration at 32%g, the shear wall remained undamaged whereas the transfer plate was severely damaged. An experiment has revealed that the transfer plate system has insufficient strength to resist possible strong earthquake action.

Publisher Summary Phenylethanolamine-N-methyltransferase (PNMT) is both neurally and hormonally regulated like other enzymes involved in catecholamine biosynthesis. In the adrenal medulla, the major source of peripheral catecholamines, PNMT expression is neurally controlled via the splanchnic nerve, which provides cholinergic innervation to the medulla. Administration of the catecholamine reuptake inhibitor—reserpine—leads to reflex stimulation of the splanchnic nerve and a rise in PNMT enzymatic activity and mRNA. The molecular mechanism for the neural activation of PNMT gene expression, beginning with cholinergic receptor activation through PNMT gene activation, remains to be elucidated. If RS1 cells, derived from the PC12 cell line, are transiently transfected with a PNMT promoter-reporter gene construct, pRP863LUC, consisting of the proximal 863 bp of PNMT promoter-regulatory sequences linked to the firefly luciferase gene, and a functional Egr-1 expression construct, pCMVEgr-1, Egr-1 activates the PNMT promoter to stimulate luciferase expression as much as four- to fivefold. Gel mobility shift assays in the presence of an anti-Egr-1 antibody confirm that Egr-1 protein will complex with 21 bp oligonucleotides, encoding these Egr-1 binding sites. To examine whether Egr-1 might mediate the neural activation of the PNMT gene, the effects of the cholinergic agonist, carbachol (CCh), on luciferase reporter gene expression and Egr-1 mRNA were examined. Carbachol induced a time-dependent rise in luciferase, with a peak 1.5-fold induction at 6 hr, after which luciferase activity declined and returned to basal levels by 36 hr. To provide further evidence for the role of Egr-1 in the neural control of PNMT gene expression, the effects of CCh on PNMT promoter activity was examined when the Egr-1 binding site was mutated. Only in the case of neural activation by metrazole are quantitative and temporal changes in Egr-I and PNMT mRNA consistent with Egr-1 acting as a transcriptional activator of PNMT gene expression.

Publisher Summary This chapter presents the main novel findings concerning human fetal astrocyte tumor necrosis factor receptors (TNF-Rs) and nitric oxide (NO). The focus is on interleukin-1β (IL-1β) and Interferon-γ (IFN-γ) treatment that leads to increased soluble TNF-R concentrations in astrocyte supernatants without a detectable change in surface TNF-Rs, the inhibition of cytokine-induced soluble TNF-Rs by pentoxifylline (PTX); but it does not affect surface TNF-R, the association of elevated soluble TNF-R levels with increased TNF and NO production. It is concluded that during CNS inflammation, such as MS, NO production is accompanied by changes in TNF-Rs, which may either limit or prolong the effects that NO has on surrounding cells or invading pathogens. Indeed, NO concentrations may be regulated, in part, by modulating TNF-R shedding. Recent findings suggest that TNF effects on a target cell are mediated, in part, by the presence of soluble extracellular TNF receptor (TNF-R) fragments cleaved from intact surface receptors by proteases. These soluble TNF-Rs can bind to TNF and inhibit or prolong its activity, and are additional pathways by which TNF can be modulated. Thus, the maintenance of NO levels within a nonpathological range may depend not only on limiting inducible nitric oxide synthase (iNOS), but also on regulating cytokine pathways associated with iNOS activation. One of the aims of the chapter is to discuss the evidence of the production and regulation of TNF, TNF-Rs, and NO production in human glial cell cultures. These studies are based on the hypothesis that TNF, IL-1, and NO mediate demyelination in multiple sclerosis (MS) plaques and neuronal damage in acquired immunodeficiency syndrome (AIDS) dementia, both of which may contribute to the clinical manifestations of these conditions.

Publisher Summary Metacognition is an important construct in reading research and metacognitive strategies have been shown to differentiate between skilled and unskilled readers. Reading researchers have shown that teaching students metacognitive strategies in reading enhanced their reading comprehension. This chapter discusses the relevance of metacognition to learning disabilities. This relevance concerns the invalidity in interpreting all learning and performance problems in individuals with learning disabilities as deep-seated cognitive deficiencies as well as the necessity to include metacognitive strategies in reading and writing in instructional remediations of those individuals. The relevance of metacognition to learning disabilities is realized through an appreciation of A. L. Brown's conceptualization of the crucial role of metacognition in successful reading and learning and of the empirical research on metacognitive skills in reading that discriminated among younger readers, poor readers, and skilled readers.

The levels of rat adrenal phenylethanolamine N -methyltransferase fall dramatically following hypophysectomy and can be restored to normal values by the administration of adrenocorticotrophin or glucocorticoids. Studies using combined radiolabeling and immunochemical techniques reveal that hypophysectomy accelerates degradation of the enzyme and that proteolysis of the enzyme in vivo is under regulation by glucocorticoids. After hypophysectomy the stability of phenylethanolamine N -methyltransferase at 50° is profoundly reduced, suggesting that concomitant with the increased susceptibility of the enzyme to proteolysis in vivo is an enhanced vulnerability to thermal denaturation in vitro . The thermal stability of the enzyme seems to be regulated by a freezing-thawinglabile, dialyzable substance present in the adrenal glands of normal rats. This material, termed stabilizing factor, is lost after hypophysectomy and can be restored by the administration of ACTH or dexamethasone. The stabilizing factor appears to act by binding to phenylethanolamine N -methyltransferase and can be dissociated from the immunoadsorbed enzyme by washing. The partially purified stabilizing factor has an absorption maximum at 264 nm; preliminary results indicate that it may be S -adenosylmethionine. Thus it is possible that binding of the enzyme to S -adenosylmethionine confers stability against proteolysis in vivo and thermal denaturation in vitro .