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Humans form lasting memories of stimuli that were only encountered once. This naturally occurs when listening to a story, however it remains unclear how and when memories are stored and retrieved during story-listening. Here, we first confirm in behavioral experiments that participants can learn about the structure of a story after a single exposure and are able to recall upcoming words when the story is presented again. We then track mnemonic information in high frequency activity (70-200 Hz) as patients undergoing electrocorticographic recordings listen twice to the same story. We demonstrate predictive recall of upcoming information through neural responses in auditory processing regions. This neural measure correlates with behavioral measures of event segmentation and learning. Event boundaries are linked to information flow from cortex to hippocampus. When listening for a second time, information flow from hippocampus to cortex precedes moments of predictive recall. These results provide insight on a fine-grained temporal scale into how episodic memory encoding and retrieval work under naturalistic conditions., (© 2021. The Author(s).)

A defining aspect of human cognition is the ability to integrate conceptual information into complex semantic combinations. For example, we can comprehend "plaid" and "jacket" as individual concepts, but we can also effortlessly combine these concepts to form the semantic representation of "plaid jacket." Many neuroanatomic models of semantic memory propose that heteromodal cortical hubs integrate distributed semantic features into coherent representations. However, little work has specifically examined these proposed integrative mechanisms and the causal role of these regions in semantic integration. Here, we test the hypothesis that the angular gyrus (AG) is critical for integrating semantic information by applying high-definition transcranial direct current stimulation (tDCS) to an fMRI-guided region-of-interest in the left AG. We found that anodal stimulation to the left AG modulated semantic integration but had no effect on a letter-string control task. Specifically, anodal stimulation to the left AG resulted in faster comprehension of semantically meaningful combinations like "tiny radish" relative to non-meaningful combinations, such as "fast blueberry," when compared to the effects observed during sham stimulation and stimulation to a right-hemisphere control brain region. Moreover, the size of the effect from brain stimulation correlated with the degree of semantic coherence between the word pairs. These findings demonstrate that the left AG plays a causal role in the integration of lexical-semantic information, and that high-definition tDCS to an associative cortical hub can selectively modulate integrative processes in semantic memory., Significance Statement: A major goal of neuroscience is to understand the neural basis of behaviors that are fundamental to human intelligence. One essential behavior is the ability to integrate conceptual knowledge from semantic memory, allowing us to construct an almost unlimited number of complex concepts from a limited set of basic constituents (e.g., "leaf" and "wet" can be combined into the more complex representation "wet leaf"). Here, we present a novel approach to studying integrative processes in semantic memory by applying focal brain stimulation to a heteromodal cortical hub implicated in semantic processing. Our findings demonstrate a causal role of the left angular gyrus in lexical-semantic integration and provide motivation for novel therapeutic applications in patients with lexical-semantic deficits., (Copyright © 2016 the authors 0270-6474/16/363829-10$15.00/0.)

Semantic representations capture the statistics of experience and store this information in memory. A fundamental component of this memory system is knowledge of the visual environment, including knowledge of objects and their associations. Visual semantic information underlies a range of behaviors, from perceptual categorization to cognitive processes such as language and reasoning. Here we examine the neuroanatomic system that encodes visual semantics. Across three experiments, we found converging evidence indicating that knowledge of verbally mediated visual concepts relies on information encoded in a region of the ventral-medial temporal lobe centered on parahippocampal cortex. In an fMRI study, this region was strongly engaged by the processing of concepts relying on visual knowledge but not by concepts relying on other sensory modalities. In a study of patients with the semantic variant of primary progressive aphasia (semantic dementia), atrophy that encompassed this region was associated with a specific impairment in verbally mediated visual semantic knowledge. Finally, in a structural study of healthy adults from the fMRI experiment, gray matter density in this region related to individual variability in the processing of visual concepts. The anatomic location of these findings aligns with recent work linking the ventral-medial temporal lobe with high-level visual representation, contextual associations, and reasoning through imagination. Together, this work suggests a critical role for parahippocampal cortex in linking the visual environment with knowledge systems in the human brain.

Background: Transcranial direct current stimulation (tDCS) is a brain stimulation technique used to examine causal relationships between brain regions and cognitive functions. The effects from tDCS are complex, and the extent to which stimulation reliably affects different cognitive domains is not fully understood and continues to be debated., Objective/hypothesis: To conduct a meta-analysis of studies examining the effects of single-session anodal tDCS on language., Methods: The meta-analysis examined the behavioral results from eleven experiments of single-session anodal tDCS and language processing in healthy adults. The means and standard deviations of the outcome measures were extracted from each experiment and entered into the meta-analyses. In the first analysis, we examined the effects of single-session tDCS across all language studies. Next, a series of sub-analyses examined the effects of tDCS on specific tasks and stimulation protocols., Results: There was a significant effect from anodal single-session tDCS in healthy adults compared to sham (P = 0.001) across all language measures. Next, we found significant effects on specific stimulation protocols (e.g., offline measures, P = 0.002), as well as specific tasks and electrode montages (e.g., verbal fluency measures and left prefrontal cortex, P = 0.035)., Conclusions: The results indicate that single-session tDCS produces significant and reliable effects on language measures in healthy adults., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Amyloid-β (Aβ) 42 has been implicated as the initiating molecule in the pathogenesis of Alzheimer's disease (AD); thus, therapeutic strategies that target Aβ42 are of great interest. γ-Secretase modulators (GSMs) are small molecules that selectively decrease Aβ42. We have previously reported that many acidic steroids are GSMs with potencies ranging in the low to mid micromolar concentration with 5β-cholanic acid being the most potent steroid identified GSM with half maximal effective concentration (EC50) of 5.7 μM., Results: We find that the endogenous cholesterol metabolite, 3β-hydroxy-5-cholestenoic acid (CA), is a steroid GSM with enhanced potency (EC50 of 250 nM) relative to 5β-cholanic acid. CA i) is found in human plasma at ~100-300 nM concentrations ii) has the typical acidic GSM signature of decreasing Aβ42 and increasing Aβ38 levels iii) is active in in vitro γ-secretase assay iv) is made in the brain. To test if CA acts as an endogenous GSM, we used Cyp27a1 knockout (Cyp27a1-/-) and Cyp7b1 knockout (Cyp7b1-/-) mice to investigate if manipulation of cholesterol metabolism pathways relevant to CA formation would affect brain Aβ42 levels. Our data show that Cyp27a1-/- had increased brain Aβ42, whereas Cyp7b1-/- mice had decreased brain Aβ42 levels; however, peripheral dosing of up to 100 mg/kg CA did not affect brain Aβ levels. Structure-activity relationship (SAR) studies with multiple known and novel CA analogs studies failed to reveal CA analogs with increased potency., Conclusion: These data suggest that CA may act as an endogenous GSM within the brain. Although it is conceptually attractive to try and increase the levels of CA in the brain for prevention of AD, our data suggest that this will not be easily accomplished.

The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid-β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 (CRFR1) and γ-secretase internalization. Co-immunoprecipitation studies establish that γ-secretase associates with CRFR1; this is mediated by β-arrestin binding motifs. Additionally, CRFR1 and γ-secretase co-localize in lipid raft fractions, with increased γ-secretase accumulation upon CRF treatment. CRF treatment also increases γ-secretase activity in vitro, revealing a second, receptor-independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ-secretase activity. Unexpectedly, CRFR1 antagonists also increased Aβ. These data collectively link CRF to increased Aβ through γ-secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aβ and in some cases preferentially increase Aβ42 via complex effects on γ-secretase., (© 2015 The Authors.)

Human thought and language rely on the brain's ability to combine conceptual information. This fundamental process supports the construction of complex concepts from basic constituents. For example, both "jacket" and "plaid" can be represented as individual concepts, but they can also be integrated to form the more complex representation "plaid jacket." Although this process is central to the expression and comprehension of language, little is known about its neural basis. Here we present evidence for a neuroanatomic model of conceptual combination from three experiments. We predicted that the highly integrative region of heteromodal association cortex in the angular gyrus would be critical for conceptual combination, given its anatomic connectivity and its strong association with semantic memory in functional neuroimaging studies. Consistent with this hypothesis, we found that the process of combining concepts to form meaningful representations specifically modulates neural activity in the angular gyrus of healthy adults, independent of the modality of the semantic content integrated. We also found that individual differences in the structure of the angular gyrus in healthy adults are related to variability in behavioral performance on the conceptual combination task. Finally, in a group of patients with neurodegenerative disease, we found that the degree of atrophy in the angular gyrus is specifically related to impaired performance on combinatorial processing. These converging anatomic findings are consistent with a critical role for the angular gyrus in conceptual combination., (Copyright © 2015 the authors 0270-6474/15/353276-09$15.00/0.)

Cooperation between a journal editor and the federal Office of Research Integrity (ORI) in addressing investigations of research misconduct, each performing their own responsibilities while keeping each other informed of events and evidence, can be critical to the professional and regulatory resolution of a case. This paper describes the history of one of ORI's most contentious investigations that involved falsification of research on Parkinson's disease patients by James Abbs, Professor of Neurology, University of Wisconsin, published in the journal Neurology, which was handled cooperatively by the authors, who were the chief ORI investigator and the Editor-in-Chief of Neurology, respectively.

Rapid environmental assessment (REA) involves scoring abundances of ecosystems/species groups and magnitude of pressures, concurrently, using the same logarithmic (0-6) assessment scale. We demonstrate the utility of REA data for an alert system identifying different levels of coastal management concern. Thresholds set for abundances/magnitudes, when crossed, trigger proposed responses. Kerkennah, Tunisia, our case study, has significant natural assets (e.g. exceptional seagrass and invertebrate abundances), subjected to varying levels of disturbance and management concern. Using REA thresholds set, fishing, green algae/eutrophication and oil occurred at 'low' levels (scores 0-1): management not (currently) necessary. Construction and wood litter prevailed at 'moderate' levels (scores 2-4): management alerted for (further) monitoring. Solid waste densities were 'high' (scores 5-6): management alerted for action; quantities of rubbish were substantial (20-200 items m⁻¹ beach) but not unprecedented. REA is considered a robust methodology and complementary to other rapid assessment techniques, environmental frameworks and indicators of ecosystem condition., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The Red Sea is among the world's top marine biodiversity hotspots. We re-examined coastal ecosystems at sites surveyed during the 1980s using the same methodology. Coral cover increased significantly towards the north, mirroring the reverse pattern for mangroves and other sedimentary ecosystems. Latitudinal patterns are broadly consistent across both surveys and with results from independent studies. Coral cover showed greatest change, declining significantly from a median score of 4 (1000-9999 m(2)) to 2 (10-99m(2)) per quadrat in 2010/11. This may partly reflect impact from coastal construction, which was evident at 40% of sites and has significantly increased in magnitude over 30 years. Beach oil has significantly declined, but shore debris has increased significantly. Although substantial, levels are lower than at some remote ocean atolls. While earlier reports have suggested that the Red Sea is generally healthy, shifting environmental baselines are evident from the current study., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aggregation and accumulation of Aβ42 play an initiating role in Alzheimer's disease (AD); thus, selective lowering of Aβ42 by γ-secretase modulators (GSMs) remains a promising approach to AD therapy. Based on evidence suggesting that steroids may influence Aβ production, we screened 170 steroids at 10 μM for effects on Aβ42 secreted from human APP-overexpressing Chinese hamster ovary cells. Many acidic steroids lowered Aβ42, whereas many nonacidic steroids actually raised Aβ42. Studies on the more potent compounds showed that Aβ42-lowering steroids were bonafide GSMs and Aβ42-raising steroids were inverse GSMs. The most potent steroid GSM identified was 5β-cholanic acid (EC50=5.7 μM; its endogenous analog lithocholic acid was virtually equipotent), and the most potent inverse GSM identified was 4-androsten-3-one-17β-carboxylic acid ethyl ester (EC50=6.25 μM). In addition, we found that both estrogen and progesterone are weak inverse GSMs with further complex effects on APP processing. These data suggest that certain endogenous steroids may have the potential to act as GSMs and add to the evidence that cholesterol, cholesterol metabolites, and other steroids may play a role in modulating Aβ production and thus risk for AD. They also indicate that acidic steroids might serve as potential therapeutic leads for drug optimization/development.

Cramer et al. (Reports, 23 March 2012, p. 1503; published online 9 February 2012) demonstrates short-term bexarotene treatment clearing preexisting β-amyloid deposits from the brains of APP/PS1ΔE9 mice with low amyloid burden, providing a rationale for repurposing this anticancer agent as an Alzheimer's disease (AD) therapeutic. Using a nearly identical treatment regimen, we were unable to detect any evidence of drug efficacy despite demonstration of target engagement.

Misconduct in science and research became the subject of significant public attention and Congressional scrutiny beginning in the 1970s and 1980s, which led to public statements, policies, and finally formal federal regulations being promulgated by Government agency officials. The Office of Research Integrity (ORI) in the Department of Health and Human Services was a major and very visible component of this process. This article provides a detailed history of the first two decades of federal research misconduct regulations and of ORI's history (under extremely difficult and unfair challenges), including personal views by the former ORI chief investigator and associate director.

Inspired by marine cyanobacterial natural products, we synthesized modified peptides with a central statine-core unit, characteristic for aspartic protease inhibition. A series of tasiamide B analogues inhibited BACE1, a therapeutic target in Alzheimer's disease. We probed the stereospecificity of target engagement and determined additional structure-activity relationships with respect to BACE1 and related aspartic proteases, cathepsins D and E. We cocrystallized selected inhibitors with BACE1 to reveal the structural basis for the activity. Hybrid molecules that combine features of tasiamide B and an isophthalic acid moiety-containing sulfonamide showed nanomolar cellular activity. Compounds were screened in a series of rigorous complementary cell-based assays. We measured secreted APP ectodomain (sAPPβ), membrane bound carboxyl terminal fragment (CTF), levels of β-amyloid (Aβ) peptides and selectivity for β-secretase (BACE1) over γ-secretase. Prioritized compounds showed reasonable stability in vitro and in vivo, and our most potent inhibitor showed efficacy in reducing Aβ levels in the rodent brain.

The Chagos Archipelago was designated a no-take marine protected area (MPA) in 2010; it covers 550 000 km 2 , with more than 60 000 km 2 shallow limestone platform and reefs. This has doubled the global cover of such MPAs.It contains 25-50% of the Indian Ocean reef area remaining in excellent condition, as well as the world's largest contiguous undamaged reef area. It has suffered from warming episodes, but after the most severe mortality event of 1998, coral cover was restored after 10 years.Coral reef fishes are orders of magnitude more abundant than in other Indian Ocean locations, regardless of whether the latter are fished or protected.Coral diseases are extremely low, and no invasive marine species are known.Genetically, Chagos marine species are part of the Western Indian Ocean, and Chagos serves as a 'stepping-stone' in the ocean.The no-take MPA extends to the 200 nm boundary, and. includes 86 unfished seamounts and 243 deep knolls as well as encompassing important pelagic species.On the larger islands, native plants, coconut crabs, bird and turtle colonies were largely destroyed in plantation times, but several smaller islands are in relatively undamaged state.There are now 10 'important bird areas', coconut crab density is high and numbers of green and hawksbill turtles are recovering.Diego Garcia atoll contains a military facility; this atoll contains one Ramsar site and several 'strict nature reserves'. Pollutant monitoring shows it to be the least polluted inhabited atoll in the world. Today, strict environmental regulations are enforced.Shoreline erosion is significant in many places. Its economic cost in the inhabited part of Diego Garcia is very high, but all islands are vulnerable.Chagos is ideally situated for several monitoring programmes, and use is increasingly being made of the archipelago for this purpose.

This review examines the substantial changes that have taken place in marine habitats and resources of the Gulf over the past decade. The habitats are especially interesting because of the naturally high levels of temperature and salinity stress they experience, which is important in a changing world climate. However, the extent of all natural habitats is changing and their condition deteriorating because of the rapid development of the region and, in some cases from severe, episodic warming episodes. Major impacts come from numerous industrial, infrastructure-based, and residential and tourism development activities, which together combine, synergistically in some cases, to cause the observed deterioration in most benthic habitats. Substantial sea bottom dredging for material and its deposition in shallow water to extend land or to form a basis for huge developments, directly removes large areas of shallow, productive habitat, though in some cases the most important effect is the accompanying sedimentation or changes to water flows and conditions. The large scale of the activities compared to the relatively shallow and small size of the water body is a particularly important issue. Important from the perspective of controlling damaging effects is the limited cross-border collaboration and even intra-country collaboration among government agencies and large projects. Along with the accumulative nature of impacts that occur, even where each project receives environmental assessment or attention, each is treated more or less alone, rarely in combination. However, their combination in such a small, biologically interacting sea exacerbates the overall deterioration. Very few similar areas exist which face such a high concentration of disturbance, and the prognosis for the Gulf continuing to provide abundant natural resources is poor., (Copyright 2009. Published by Elsevier Ltd.)

The tuning of parameters in climate models is essential to provide reliable long-term forecasts of Earth system behaviour. We apply a multi-objective optimization algorithm to the problem of parameter estimation in climate models. This optimization process involves the iterative evaluation of response surface models (RSMs), followed by the execution of multiple Earth system simulations. These computations require an infrastructure that provides high-performance computing for building and searching the RSMs and high-throughput computing for the concurrent evaluation of a large number of models. Grid computing technology is therefore essential to make this algorithm practical for members of the GENIE project.

We have used the Grid ENabled Integrated Earth system modelling framework to study the archetypal example of a tipping point in the climate system; a threshold for the collapse of the Atlantic thermohaline circulation (THC). eScience has been invaluable in this work and we explain how we have made it work for us. Two stable states of the THC have been found to coexist, under the same boundary conditions, in a hierarchy of models. The climate forcing required to collapse the THC and the reversibility or irreversibility of such a collapse depends on uncertain model parameters. Automated methods have been used to assimilate observational data to constrain the pertinent parameters. Anthropogenic climate forcing leads to a robust weakening of the THC and increases the probability of crossing a THC tipping point, but some ensemble members collapse readily, whereas others are extremely resistant. Hence, we test general methods that have been developed to directly diagnose, from time-series data, the proximity of a 'tipping element', such as the THC to a bifurcation point. In a three-dimensional ocean-atmosphere model exhibiting THC hysteresis, despite high variability in the THC driven by the dynamical atmosphere, some early warning of an approaching tipping point appears possible.

Gene transfer to lung has been hindered by inflammatory and immunological responses activated to the gene-transfer agent or transgene products. In prior work, adenovirus vector delivered to the lung with the cationic glucocorticoid, dexamethasone-spermine (DS) had improved targeting to conducting airway epithelium and reduced cellular infiltration. In this study, the effect of formulation on homologous adenovirus vector re-administration was studied in C57Bl/6 mice. Formulation of an adenovirus vector expressing LacZ with DS/dioleoylphosphatidylethanolamine (DOPE) delivered at day 0 allowed re-administration of adenovirus vector expressing alkaline phosphatase at day 21. Formulation with 3beta [N-(N', N'-dimethylaminoethane) carbamoy] cholesterol (DC-Chol) DC-cholesterol (DC-Chol))/DOPE or dexamethasone in the first dosing at day 0 resulted in moderate alkaline phosphatase expression at day 24. Neutralizing antibodies against adenovirus vector in serum at day 28 were greatly reduced by all three formulations in mice receiving a single dose of adenovirus at day 0. Also, homologous adenovirus vector re-administration at day 14 produced less neutralizing antibody at day 28 when adenovirus was formulated with DS/DOPE at day 0. The use of DS/DOPE at day 0 dramatically reduced CD4 and CD8 T-cell infiltration in mice receiving adenovirus at day 0 followed by vector re-administration at day 14. Transgene-specific T-cell activation was markedly reduced by the DC-Chol/DOPE formulation. Overall, DS/DOPE) facilitated homologous vector re-administration through a combination of liposomal and glucocorticoid mechanisms.

Microvascular abnormalities are associated with and causative of the development of end-stage organ complications in adult diabetic patients. Whether the same microvascular abnormalities are present in pediatric patients is not known and has not been studied because of a lack of real-time technology, methodology to study young patients, and availability of an appropriate noninvasive site for in vivo studies. We hypothesized that microvascular abnormalities should be present in pediatric patients despite their young age and the relatively short durations of the disease. In this study, computer-assisted intravital microscopy (CAIM) was adapted to blindly quantify microvascular abnormalities in 12 pediatric type 1 diabetic mellitus (T1DM) patients (ages = 6-16 years; mean +/- SD = 11.42 +/- 3.42; duration since diagnosis = 2-14 years; mean +/- SD = 6.75 +/- 3.79) in vivo, using the microcirculation of the bulbar conjunctiva as a noninvasive site. Microvascular abnormalities, commonly found in adult patients, existed in the conjunctival microcirculation of all pediatric T1DM patients in varying degrees despite their relatively young age. A severity index (SI) was developed to reflect the cumulative severity of the microvascular abnormalities and was computed as the summation of all microvascular abnormalities found in each patient. SI for the 12 T1DM patients (mean +/- SD = 7.42 +/- 1.88; median = 8; mode = 9) differed significantly from that for the nondiabetic controls (mean +/- SD = 0.67 +/- 0.78; median = 0.5; mode = 0; P < 0.0001). In addition, SI correlated with hemoglobin A1c levels (mean +/- SD = 9.18 +/- 1.57) of T1DM patients but did not correlate with the duration of disease since diagnosis of the same patients. This observation raises the possibility that diabetic pathogenesis may precede the onset of overt disease or clinical diagnosis. This study confirms that CAIM may represent the availability of a useful real-time technology to study conjunctival microvascular abnormalities in vascular diseases in juvenile as well as adult patients., ((c) 2002 Elsevier Science (USA).)

Biodiversity provides "raw materials" for the food chain and seafood production, and also influences the capacity of ecosystems to perform these and other services. Harvested marine seafood species now exceed 100 million t y(-1) and provide about 6% of all protein and 17% of animal protein consumed by humans. These resources include representatives from about nine biologically diverse groups of plants and animals. Fish account for most of the world"s marine catches, of which only 40 species are taken in abundance. Highest primary productivity and the richest fisheries are found within Exclusive Economic Zones (EEZ). This narrow strip (200 nautical mile/370 km wide) is not only the site of coastal "food factories" but also the area associated with heaviest perturbation to the marine environment. Structural redundancy is evident in marine ecosystems, in that many species are interchangeable in the way they characterise assemblage composition. While there is probably functional redundancy within groups, the effects of species loss on ecosystem performance cannot be easily predicted. In particular, the degree to which biodiversity per se is needed for ecosystem services, including seafood/fishery production, is poorly understood. Many human activities, including unsustainable fishing and mariculture, lead to erosion of marine biodiversity. This can undermine the biophysical cornerstones of fisheries and have other undesirable environmental side effects. Of direct concern are "species effects", in particular the removal of target and non-target fishery species, as well as conservationally important fauna. Equally disrupting but less immediate are "ecosystem effects", such as fishing down the food web, following a shift from harvested species of high to low trophic level. Physical and biological disturbances from trawl nets and dynamite fishing on coral reefs can also severely impact ecosystem structure and function. "Broadscale" biological and social effects brought about by fishing carry even more far-reaching consequences. For example, fishing itself can change the age at which sexual maturity is reached, thus affecting the reproductive status of the stock. Hence, fishing may be regarded as a mediator of evolution. Social impacts include conflicts over fish prices and policies arising from heavy fishing and inadequate institutional structures. Measures to increase the sustainability of catches and of biodiversity need to be much more tightly coupled. Promising approaches include use of bio-economic indicators and fully protected marine areas. High- and local-level governance options are also examined. Use of expert systems incorporating "fuzzy logic" are providing useful environmental insights in the ASEAN countries and other parts of the world, and have applications in fishery management and biodiversity conservation.

Pituitary adenylate cyclase-activating peptide and lysozyme are potent chemorepellents which act through the same receptor in Tetrahymena. Using in vivo behavioral studies, we have found that the pituitary adenylate cyclase-activating peptide/lysozyme receptor appears to signal through a G-protein pathway which is mediated through both adenosine 3'5'monophosphate and protein kinase C. Avoidance to pituitary adenylate cyclase-activating peptide and lysozyme is inhibited by the G-protein inhibitor, guanosine 5'-O-(2thiodiphosphate), the adenosine 3'5'monophate analog, Rp-adenosine-3', 5' cyclic monophosphorothioate, and the protein kinase C inhibitors, calphostin C and bisindolylmaleimide IV. A proposed model for signaling through the pituitary adenylate cyclase-activating peptide/lysozyme receptor is briefly outlined.

Given the concerns expressed by members of the academic and legal community about whether (and how) to handle anonymous and pseudonymous allegations of scientific misconduct, this paper summaries the experiences of the Office of Research Integrity and its predecessor from 1989 through 1997. Although the record shows that research institutions and the ORI have treated such allegations seriously, the fraction of complainants to the ORI who remain anonymous is small (8% of 986 allegations); few anonymous complaints are sufficiently substantive to be pursued (4% of the 357 formal cases opened in the ORI); and only 1 of these 13 cases resulted in an ORI finding of scientific misconduct.

Objective: To provide extended intra-oral delivery of a saliva substitute., Intervention: Three different types of prostheses containing saliva substitute were designed and assessed: a two-part device resembling a mandibular complete denture sealed by cobalt-samerium magnets, a one-part clear resin device for the edentate patients and a flexible mouth guard type of appliance containing a lubricant releasing bubble for the dentate patients., Setting: A teaching hospital Oral Medicine and Rheumatology Clinic., Subjects: 8 edentate and 3 dentate Sjogren Syndrome sufferers., Outcome Measures: Subjective dryness after a week of wearing the lubricating appliance., Results: The majority of the subjects wore the appliances for 6-12 hours during each 24 hours. The initial dryness severity diminished after wearing the lubricating prosthesis. The patients preferred to wear the appliance at night., Conclusion: All criteria were fulfilled on designing a saliva substitute lubricating appliance and some of the subjects have worn this prosthesis successfully for up to 3 years. Particular benefit was obtained by night-time wear.

Many allegations of scientific misconduct result from activities that are perceived by the complainants as the "theft" of ideas, experimental results, or other intellectual property. The authors' thesis is that many of these allegations originate in misconceptions about the ownership of publicly supported scientific research. Some universities and medical schools may have their own codes for authorship, and journals and professional societies have codes or guidelines. In the NIH intramural programs, research data are considered to be the property of the institutes, not the individual researchers. In contrast, the training and experience of most scientists lead them to consider research data as being theirs. The paper discusses the origins of this attitude toward data and the ways that the structures of university laboratories and training programs lead to confusion and misunderstandings of researchers' "rights" to data. Also, emotional and personality factors often complicate these issues and lead to confrontations. Other misconceptions widely held among researchers: the false concepts of "my grant" and the "co-principal" investigator, ideas about who is and is not qualified to be an author, and ideas about sharing data. The authors emphasize the importance of scientifically literate legal advisers and the necessity for graduate students, postdoctoral fellows, and professors to understand their institutions' and grantors' guidelines and their obligations as scientists. At the heart of these obligations at all levels of research is honesty.

The theory of aging which proposes that DNA repair capacity declines with age and/or DNA damage accumulates with age, resulting in increasingly aberrant gene expression, is attractive but still unproven. Most results that do not support the theory are at least neutral. We propose that much of the ambiguity produced by work so far is due to (a) the difficulty of controlling all relevant variables, including particularly the proliferation state of the cells used and the location and nature of the damage being repaired, and (b) the existence of multiple and overlapping DNA repair pathways. A better knowledge of the critical, rate-limiting events in DNA repair in vivo, and the application of more sophisticated approaches for studying these events, may ultimately resolve the ambiguities. The causal relationship between DNA damage and cancer seems more secure. Declining DNA repair capacity with age would be expected to accelerate the increased incidence of cancer with age, but it is not known how important this is compared to other genetic and environmental variables. Results with genetic diseases generally support this view. Diseases characterized by DNA repair deficiencies are accompanied by phenomena that are also characteristic of normal aging, but a causal relationship has not been established. However, some of these diseases do constitute a strong risk factor for cancer. Even less convincing is a causal link between DNA repair deficiencies and aging in the so-called premature aging syndromes.

Degradation of uracil-containing DNA by Bacillus subtilis extracts and its inhibition after infection by the uracil-containing DNA phage PBS2 have been investigated to resolve differences between the published reports of Tomita and Takahashi (1975) and Friedberg et al. (1975, 1976). The product of hydrolysis of PBS2 DNA, tritium labeled in its uracil and cytosine residues, is solely uracil and not deoxyuridine. The degrading activity is completely inhibited within 7 min after PBS2 infection, before any other known PBS2-induced protein is detectable. The production of the PBS2 inhibitor (a small, heat-stable protein) continues until 10 to 20 min postinfection.

In vivo studies of PBS2 phage replication in a temperature-sensitive Bacillus subtilis DNA polymerase III (Pol III) mutant and a temperature-resistant revertant of this mutant have suggested the possible involvement of Pol III in PBS2 DNA synthesis. Previous results with 6-(p-hydroxyphenylazo)-uracil (HPUra), a specific inhibitor of Pol III and DNA replication in uninfected cells, suggest that Pol III is not involved in phage DNA replication, due to its resistance to this drug. Experiments were designed to examine possible explanations for this apparent contradiction. First, assays of the host Pol III and the phage-induced DNA polymerase activities in extracts indicated that a labile Pol III did not result in a labile phage-induced enzyme, suggesting that this new polymerase is not a modified HPUra-resistant form of Pol III. Indeed the purified phage-induced enzyme was resistant to the active, reduced form of HPUra under all assay conditions tested. Since in vitro Pol III was capable of replicating the uracil-containing DNA found in this phage, the sensitivity of the purified enzyme to reduced HPUra was examined using phage DNA as template-primer and dUTP as substrate; these new substrates did not affect the sensitivity of the host enzyme to the drug.

Bacillus subtilis grown at temperatures below 37 degrees contains two thymidylate synthetases, TSaseA and TSaseB. Their presence is dependent on functional thyA and thyB genes, respectively. When cells are grown at 46 degrees they only contain TSaseA activity. This allous an easy positive selection for thyA and thyA, THYB mutants. The two TSases have been physically separated, and they show similar overall requirements for activity. However, they differ significantly in both their kinetic and their physicochemical properties.

Mutants of bacteriophage phie inducing only 1 to 5% of wild-type levels of dTTP-dUTP nucleotidohydrolase give normal bursts of viable progeny phage whose DNA contains 5 to 10% thymine (but no uracil) in place of 5-hydroxymethyluracil. The relative heat lability of one phage mutant enzyme solubilized from the membrane fraction of infected cells suggests that a phie gene codes for the induced dTTPase-dUTPase.

Bacteriophage PBS2 replication is unaffected by rifampicin and other rifamycin derivatives, which are potent inhibitors of Bacillus subtilis RNA synthesis. Extracts of gently-lysed infected cells contain a DNA-dependent RNA polymerase activity which is specific for uracil-containing PBS2 DNA. The PBS2-induced RNA polymerase is insensitive to rifamycin derivatives which inhibit the host's RNA polymerase.

The DNA polymerase induced by Bacillus subtilis bacteriophage PBS2 (whose DNA contains uracil instead of thymine) has been purified and characterized for its specificity. The enzyme requires a high ionic strength for optimal stability and activity and is sensitive to various anions and to sulfhdryl reagents. Both dUTP and dTTP are incorporated efficiently as substrates and are competitive inhibitors at the same active site. The apparent Km and Ki values are about 6 micrometers for dTTP and 15 micrometers for dUTP, when denatured, uracil-containing B. subtilis or salmon sperm DNA (3.9 micrometers for dUTP and 2.6 micrometers for dTTP). The PBS2 enzyme works best on denatured DNA, on double-stranded DNA activated by DNase to produce gaps, or on primed homopolymeric DNA. Using denatured DNA preparations of average molecular weight 6.2 million, the apparent Km values are 270 micrograms/ml for B. subtilis DNA and 360 micrograms/ml for PBS2 DNA; the Vmax value for denatured PBS2 DNA containing uracil is 7-fold greater than that for denatured B. subtilis DNA containing thymine. However, lower molecular weight DNAs have 10-fold lower apparent Km values and show similar Vmax values for both B. subtilis and PBS2 DNAs. Thus, the PBS2 phage-induced DNA polymerase (which likely replicates only uracil-containing phage DNA using dUTP in vivo) has little selectivity for uracil- versus thymine-containing deoxyribonucleotides or DNA in vitro.

Dextran sulfate is commonly used with polyethylene glycol to concentrate viruses before extraction of their DNA. However, dextran slulfate then easily contaminated such DNA and acted as a potent inhibitor of DNA polymerases from Bacillus subtilis (III), phage PBS2, and phage T4. Dextran sulfate only weakly inhibited Micrococcus luteus and Escherichia coli DNA polymerase I preparations.