Search

Background Insulin transport across the blood-brain barrier (BBB) is a highly regulated, saturable process, known to be affected by many peripheral substrates including insulin itself and triglycerides. This is in contrast to insulin leakage into peripheral tissues. Whether the central nervous system (CNS) can control the rate of insulin uptake by brain remains to be determined. Insulin BBB interactions are impaired in Alzheimer’s disease (AD) and CNS insulin resistance is widely prevalent in AD. Therefore, if CNS insulin controls the rate of insulin transport across the BBB, then the defective transport of insulin seen in AD could be one manifestation of the resistance to CNS insulin observed in AD. Methods We investigated whether enhancing CNS insulin levels or induction of CNS insulin resistance using an inhibitor of the insulin receptor altered the blood-to-brain transport of radioactively labeled insulin in young, healthy mice. Results We found that insulin injected directly into the brain decreased insulin transport across the BBB for whole brain and the olfactory bulb in male mice, whereas insulin receptor blockade decreased transport in female mice for whole brain and hypothalamus. Intranasal insulin, currently being investigated as a treatment in AD patients, decreased transport across the BBB of the hypothalamus. Conclusions These results suggest CNS insulin can control the rate of insulin brain uptake, connecting CNS insulin resistance to the rate of insulin transport across the BBB.

Fully shaped, morphologically standardized bone tools are generally considered reliable indicators of the emergence of modern behavior. We report the discovery of 23 double-beveled bone tools from ~ 80,000–60,000-year-old archaeological layers at Sibudu Cave in KwaZulu-Natal, South Africa. We analyzed the texture of use-wear on the archaeological bone tools, and on bone tool replicas experimentally used in debarking trees, processing rabbit pelts with and without an ochre compound, digging in sediment in and outside a cave, and on ethnographic artefacts. Debarking trees and digging in humus-rich soil produce use-wear patterns closely matching those observed on most Sibudu tools. This tool type is associated with three different Middle Stone Age cultural traditions at Sibudu that span 20,000 years, yet they are absent at contemporaneous sites. Our results support a scenario in which some southern African early modern human groups developed and locally maintained specific, highly standardized cultural traits while sharing others at a sub-continental scale. We demonstrate that technological and texture analyses are effective means by which to infer past behaviors and assess the significance of prehistoric cultural innovations.

It is unclear whether severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019, can enter the brain. Severe acute respiratory syndrome coronavirus 2 binds to cells via the S1 subunit of its spike protein. We show that intravenously injected radioiodinated S1 (I-S1) readily crossed the blood-brain barrier in male mice, was taken up by brain regions and entered the parenchymal brain space. I-S1 was also taken up by the lung, spleen, kidney and liver. Intranasally administered I-S1 also entered the brain, although at levels roughly ten times lower than after intravenous administration. APOE genotype and sex did not affect whole-brain I-S1 uptake but had variable effects on uptake by the olfactory bulb, liver, spleen and kidney. I-S1 uptake in the hippocampus and olfactory bulb was reduced by lipopolysaccharide-induced inflammation. Mechanistic studies indicated that I-S1 crosses the blood-brain barrier by adsorptive transcytosis and that murine angiotensin-converting enzyme 2 is involved in brain and lung uptake, but not in kidney, liver or spleen uptake.

We recently showed that perineuronal nets (PNNs) enmesh glucoregulatory neurons in the arcuate nucleus (Arc) of the mediobasal hypothalamus (MBH)1, but whether these PNNs play a role in either the pathogenesis of type 2 diabetes (T2D) or its treatment remains unclear. Here we show that PNN abundance within the Arc is markedly reduced in the Zucker diabetic fatty (ZDF) rat model of T2D, compared with normoglycaemic rats, correlating with altered PNN-associated sulfation patterns of chondroitin sulfate glycosaminoglycans in the MBH. Each of these PNN-associated changes is reversed following a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) at a dose that induces sustained diabetes remission in male ZDF rats. Combined with previous work localizing this FGF1 effect to the Arc area2-4, our finding that enzymatic digestion of Arc PNNs markedly shortens the duration of diabetes remission following icv FGF1 injection in these animals identifies these extracellular matrix structures as previously unrecognized participants in the mechanism underlying diabetes remission induced by the central action of FGF1.

Given a prime p, an integer $$H\in [1,p)$$, and an arbitrary set $${\mathcal {M}} \subseteq {\mathbb {F}} _p^*$$, where $${\mathbb {F}} _p$$ is the finite field with p elements, let $$J(H,{\mathcal {M}} )$$ denote the number of solutions to the congruence $$\begin{aligned} xm\equiv yn~\mathrm{mod}~ p \end{aligned}$$for which $$x,y\in [1,H]$$ and $$m,n\in {\mathcal {M}} $$. In this paper, we bound $$J(H,{\mathcal {M}} )$$ in terms of p, H, and the cardinality of $${\mathcal {M}} $$. In a wide range of parameters, this bound is optimal. We give two applications of this bound: to new estimates of trilinear character sums and to bilinear sums with Kloosterman sums, complementing some recent results of Kowalski et al. (Stratification and averaging for exponential sums: bilinear forms with generalized Kloosterman sums, 2018, arXiv:1802.09849).

We combine a classical idea of Postnikov (1956) with the method of Korobov (1974) for estimating double Weyl sums, deriving new bounds on short character sums when the modulus q has a small core Πp|qp. Using this estimate, we improve certain bounds of Gallagher (1972) and Iwaniec (1974) for the corresponding L-functions. In turn, this allows us to improve the error term in the asymptotic formula for primes in short arithmetic progressions modulo a power of a fixed prime. As yet another application of our bounds, we substantially extend the classical zero-free region (which might include Siegel zeros). Finally, we improve the previous best value $$L=\frac{12}{5}=2.2$$ of the Linnik constant for primes in arithmetic progressions modulo powers of a fixed prime to L < 2.1115.

The blood–brain barrier (BBB) was first noted for its ability to prevent the unregulated exchange of substances between the blood and the central nervous system (CNS). Over time, its characterization as an interface that enables regulated exchanges between the CNS and substances that are carried in the blood in a hormone-like fashion have emerged. Therefore, communication between the CNS, BBB and peripheral tissues has many endocrine-like properties. In this Review, I examine the various ways in which the BBB exhibits endocrine-related properties. The BBB is a target for hormones, such as leptin and insulin, that affect many of its functions. The BBB is also a secretory body, releasing substances either into the blood or the interstitial fluid of the brain. The BBB selectively allows classical and non-classical hormones entry to and exit from the CNS, thus allowing the CNS to be both an endocrine target and a secretory tissue. The BBB is affected by endocrine diseases such as diabetes mellitus and can cause or participate in endocrine diseases, including those related to thyroid hormones and obesity. The endocrine-like mechanisms of the BBB can extend the definition of endocrine disease to include neurodegenerative conditions, including Alzheimer disease, and of hormones to include cytokines, triglycerides and fatty acids. The blood–brain barrier (BBB), which is widely known as the border that separates circulating blood from the brain, is also a secretory body. This Review examines the various ways in which the BBB exhibits endocrine-related properties.

Background The microvasculature (MV) of brains with Alzheimer’s disease neuropathologic change (ADNC) and cerebral amyloid angiopathy (CAA), in the absence of concurrent pathologies (e.g., infarctions, Lewy bodies), is incompletely understood. Objective To analyze microvascular density, diameter and extracellular matrix (ECM) content in association with ADNC and CAA. Methods We examined samples of cerebral cortex and isolated brain microvasculature (MV) from subjects with the National Institute on Aging-Alzheimer's Association (NIA-AA) designations of not-, intermediate-, or high ADNC and from subjects with no CAA and moderate-severe CAA. Cases for all groups were selected with no major (territorial) strokes, ≤ 1 microinfarct in screening sections, and no Lewy body pathology. MV density and diameter were measured from cortical brain sections. Levels of basement membrane (BM) ECM components, the protein product of TNF-stimulated gene-6 (TSG-6), and the ubiquitous glycosaminoglycan hyaluronan (HA) were assayed by western blots or HA ELISA of MV lysates. Results We found no significant changes in MV density or diameter among any of the groups. Levels of BM laminin and collagen IV (col IV) were lower in MV isolated from the high ADNC vs. not-ADNC groups. In contrast, BM laminin was significantly higher in MV from the moderate-severe CAA vs. the no CAA groups. TSG-6 and HA content were higher in the presence of both high ADNC and CAA, whereas levels of BM fibronectin and perlecan were similar among all groups. Conclusions Cortical MV density and diameter are not appreciably altered by ADNC or CAA. TSG-6 and HA are increased in both ADNC and CAA, with laminin and col IV decreased in the BM of high ADNC, but laminin increased in moderate-severe CAA. These results show that changes in the ECM occur in AD and CAA, but independently of one another, and likely reflect on the regional functioning of the brain microvasculature.

Neuroimmune communication contributes to both baseline and adaptive physiological functions, as well as disease states. The vascular blood–brain barrier (BBB) and associated cells of the neurovascular unit (NVU) serve as an important interface for immune communication between the brain and periphery through the blood. Immune functions and interactions of the BBB and NVU in this context can be categorized into at least five neuroimmune axes, which include (1) immune modulation of BBB impermeability, (2) immune regulation of BBB transporters, secretions, and other functions, (3) BBB uptake and transport of immunoactive substances, (4) immune cell trafficking, and (5) BBB secretions of immunoactive substances. These axes may act separately or in concert to mediate various aspects of immune signaling at the BBB. Much of what we understand about immune axes has been from work conducted using in vitro BBB models, and recent advances in BBB and NVU modeling highlight the potential of these newer models for improving our understanding of how the brain and immune system communicate. In this review, we discuss how conventional in vitro models of the BBB have improved our understanding of the 5 neuroimmune axes. We further evaluate the existing literature on neuroimmune functions of novel in vitro BBB models, such as those derived from human induced pluripotent stem cells (iPSCs) and discuss their utility in evaluating aspects of neuroimmune communication.

Inflammation activates indoleamine 2,3-dioxygenase (IDO) which metabolizes tryptophan into kynurenine. Circulating kynurenine is transported into the brain by the large amino transporter LAT1 at the level of the blood-brain barrier. We hypothesized that administration of leucine that has a high affinity for LAT1 should prevent the entry of kynurenine into the brain and attenuate the formation of neurotoxic kynurenine metabolites. To test whether leucine could prevent inflammation-induced depression-like behavior mice were treated with lipopolysaccharide (LPS, 0.83 mg/kg IP) or saline and treated with L-leucine (50 mg/kg, IP) or vehicle administered before and 6 h after LPS. Depression-like behavior was measured by increased duration of immobility in the forced swim test and decreased sucrose preference. Leucine decreased brain kynurenine levels, blocked LPS-induced depression-like behavior and had antidepressant-like effects in control mice. Leucine had no effect of its own on sickness behavior and neuroinflammation. To confirm that leucine acts by interfering with the transport of kynurenine into the brain, mice were injected with L-leucine (300 mg/kg, IP) immediately before kynurenine (33 mg/kg IP) and brain kynurenine and depression-like behavior were measured 3 hours later. Leucine did prevent the entry of exogenous kynurenine into the brain and abrogated depression-like behavior measured by increased duration of immobility in the forced swim test. Additional experiments using an in vitro model of the blood-brain barrier confirmed that kynurenine competes with leucine at the level of the amino acid transporter LAT1 for brain uptake. These experiments also revealed that efflux was the dominant direction of kynurenine transport and was largely independent of LAT1 and leucine, which explains why leucine could block brain uptake of kynurenine without affecting brain clearance. These findings demonstrate that leucine has antidepressant properties vis-à-vis inflammation-induced depression and one mechanism for this is by blocking the ability of kynurenine to enter the brain.

Obesity is a global health problem and treatment options are still insufficient. When chronically treated with the angiotensin II receptor blocker telmisartan (TEL), rodents do not develop diet-induced obesity (DIO). However, the underlying mechanism for this is still unclear. Here we investigated whether TEL prevents leptin resistance by enhancing leptin uptake across the blood-brain barrier (BBB). To address this question, we fed C57BL/6 mice a high-fat diet (HFD) and treated them daily with TEL by oral gavage. In addition to broadly characterizing the metabolism of leptin, we determined leptin uptake into the brain by measuring BBB transport of radioactively labeled leptin after long-term and short-term TEL treatment. Additionally, we assessed BBB integrity in response to angiotensin II in vitro and in vivo. We found that HFD markedly increased body weight, energy intake, and leptin concentration but that this effect was abolished under TEL treatment. Furthermore, glucose control and, most importantly, leptin uptake across the BBB were impaired in mice on HFD, but, again, both were preserved under TEL treatment. BBB integrity was not impaired due to angiotensin II or blocking of angiotensin II receptors. However, TEL did not exhibit an acute effect on leptin uptake across the BBB. Our results confirm that TEL prevents DIO and show that TEL preserves leptin transport and thereby prevents leptin resistance. We conclude that the preservation of leptin sensitivity is, however, more a consequence than the cause of TEL preventing body weight gain.

Background Type II diabetes is a vascular risk factor for cognitive impairment and increased risk of dementia. Disruption of the blood–retinal barrier (BRB) and blood–brain barrier (BBB) are hallmarks of subsequent retinal edema and central nervous system dysfunction. However, the mechanisms by which diet or metabolic syndrome induces dysfunction are not understood. A proposed mechanism is an increase in reactive oxygen species (ROS) and oxidative stress. Inhibition of mitochondrial carbonic anhydrase (mCA) decreases ROS and oxidative stress. In this study, topiramate, a mCA inhibitor, was examined for its ability to protect the BRB and BBB in diet-induced obese type II diabetic mice. Methods BBB and BRB permeability were assessed using 14C-sucrose and 99mTc-albumin in CD-1 mice fed a low-fat (control) or a high-fat diet. Topiramate administration was compared to saline controls in both preventative and efficacy arms examining BRB and BBB disruption. Body weight and blood glucose were measured weekly and body composition was assessed using EchoMRI. Metabolic activity was measured using a comprehensive laboratory animal monitoring system. Brain tissues collected from the mice were assessed for changes in oxidative stress and tight junction proteins. Results High-fat feeding caused increased entry of 14C-sucrose and 99mTc-albumin into the brains of diet-induced obese type II diabetic mice. Increased permeability to 14C-sucrose was observed in the hypothalamus and hippocampus, and attenuated by topiramate treatment, while increased permeability to 99mTc-albumin occurred in the whole brain and was also attenuated by topiramate. Treatment with topiramate decreased measures of oxidative stress and increased expression of the tight junction proteins ZO-1 and claudin-12. In the retina, we observed increased entry of 99mTc-albumin simultaneously with increased entry into the whole brain during the preventative arm. This occurred prior to increased entry to the retina for 14C-sucrose which occurred during the efficacy arm. Treatment with topiramate had no effect on the retina. Conclusions Blood–brain barrier and blood–retinal barrier dysfunction were examined in a mouse model of diet-induced obese type II diabetes. These studies demonstrate that there are spatial and temporal differences in 14C-sucrose and 99mTc-albumin permeability in the brain and retina of diet-induced obese type II diabetic mice. Topiramate, a mitochondrial carbonic anhydrase inhibitor, is efficacious at both preventing and treating BBB disruption in this diet-induced obese type II diabetic mouse model.

Epidemiologic and in vitro studies suggest that SLCO-encoded organic anion transporting polypeptide (OATP) transporters influence the response of prostate cancer (PCa) to androgen deprivation by altering intratumor androgens. We have previously shown that castration-resistant metastases express multiple SLCO transporters at significantly higher levels than primary PCa, suggesting that OATP-mediated steroid transport is biologically relevant in advanced disease. However, whether OATP-mediated steroid transport can actually modify prostate tumor androgen levels in vivo has never been demonstrated. We sought to determine whether OATP-mediated steroid transport can measurably alter PCa androgen levels in vivo. We evaluated the uptake of dehydroepiandrosterone (DHEAS), E1S and testosterone in LNCaP cells engineered to express OATP1B1, 1B3, 2B1 or 4A1. We measured the uptake via administration of tritiated steroids to castrate mice bearing vector control or OATP1B1-, 2B1- or 4A1-expressing xenografts. We treated tumor-bearing mice with DHEAS and testosterone at physiologically relevant levels and measured intratumor accumulation of administered steroids by mass spectrometry. OATP1B1- and 2B-expressing xenografts each showed a threefold increase in tritiated-DHEAS uptake vs vector controls (P=0.002 and P=0.036, respectively). At circulating DHEAS levels similar to those in abiraterone-treated men (~15 μg dl−1), OATP1B1- and 2B1-expressing xenografts showed a 3.9-fold (P=0.057) and 1.9-fold (P=0.048) increase in tumor accumulation of DHEAS and a 1.6-fold (P=0.057) and 2.7-fold (P=0.095) increase in DHEA, respectively. At the substantial circulating testosterone levels found in eugonadal men, a consistent effect of OATP1B1, 2B1 or 4A1 on testosterone uptake in vivo was not detected. OATP transporters measurably alter DHEAS uptake and intratumor androgen levels in prostate tumors in vivo, even at circulating androgen levels achieved in abiraterone-treated patients. These novel data emphasize the continued need to inhibit ligand-mediated androgen receptor signaling in PCa tumors, and support prospective evaluation of studies designed to test inhibition of OATP-mediated DHEAS uptake and utilization.

Mild blast-induced traumatic brain injury (TBI) is associated with blood-brain barrier (BBB) disruption. However, the mechanisms whereby blast disrupts BBB integrity are not well understood. To address this issue BBB permeability to peripherally injected 14C-sucrose and 99mTc-albumin was quantified in ten brain regions at time points ranging from 0.25 to 72 hours. In mice, repetitive (2X) blast provoked BBB permeability to 14C-sucrose that persisted in specific brain regions from 0.25 to 72 hours. However, 99mTc-albumin revealed biphasic BBB disruption (open-closed-open) over the same interval, which was most pronounced in frontal cortex and hippocampus. This indicates that blast initiates interacting BBB disruption and reparative processes in specific brain regions. Further investigation of delayed (72 hour) BBB disruption revealed that claudin-5 (CLD5) expression was disrupted specifically in the hippocampus, but not in dorsal striatum, a brain region that showed no blast-induced BBB permeability to sucrose or albumin. In addition, we found that delayed BBB permeability and disrupted CLD5 expression were blocked by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). These data argue that latent nitric oxide-dependent signaling pathways initiate processes that result in delayed BBB disruption, which are manifested in a brain-region specific manner.

The blood–brain barrier (BBB) is a major impediment to the therapeutic delivery of peptides and proteins to the brain. Intranasal delivery often provides a non-invasive means to bypass the BBB. Advantages of using intranasal delivery include minimizing exposure to peripheral organs and tissues, thus reducing systemic side effects. It also allows substances that typically have rapid degradation in the blood time to exert their effect. Intranasal delivery provides the ability to target proteins and peptides to specific regions of the brain when administered with substrates like cyclodextrins. In this review, we examined the use of intranasal delivery of various proteins and peptides that have implications in the treatment of neurodegenerative diseases, focusing especially on albumin, exendin/GLP-1, GALP, insulin, leptin, and PACAP. We have described their rationale for use, distribution in the brain after intranasal injection, how intranasal administration differed from other modes of delivery, and their use in clinical trials, if applicable. Intranasal delivery of drugs, peptides, and other proteins could be very useful in the future for the prevention or treatment of brain related diseases.

Parkinson’s disease (PD) pathophysiology develops in part from the formation, transmission, and aggregation of toxic species of the protein α-synuclein (α-syn). Recent evidence suggests that extracellular vesicles (EVs) may play a vital role in the transport of toxic α-syn between brain regions. Moreover, increasing evidence has highlighted the participation of peripheral molecules, particularly inflammatory species, which may influence or exacerbate the development of PD-related changes to the central nervous system (CNS), although detailed characterization of these species remains to be completed. Despite these findings, little attention has been devoted to erythrocytes, which contain α-syn concentrations ~1000-fold higher than the cerebrospinal fluid, as a source of potentially pathogenic α-syn. Here, we demonstrate that erythrocytes produce α-syn-rich EVs, which can cross the BBB, particularly under inflammatory conditions provoked by peripheral administration of lipopolysaccharide. This transport likely occurs via adsorptive-mediated transcytosis, with EVs that transit the BBB co-localizing with brain microglia. Examination of microglial reactivity upon exposure to α-syn-containing erythrocyte EVs in vitro and in vivo revealed that uptake provoked an increase in microglial inflammatory responses. EVs derived from the erythrocytes of PD patients elicited stronger responses than did those of control subjects, suggesting that inherent characteristics of EVs arising in the periphery might contribute to, or even initiate, CNS α-syn-related pathology. These results provide new insight into the mechanisms by which the brain and periphery communicate throughout the process of synucleinopathy pathogenesis. Electronic supplementary material The online version of this article (10.1186/s40478-017-0470-4) contains supplementary material, which is available to authorized users.

A trans-agency workshop on the blood–brain interface (BBI), sponsored by the National Heart, Lung and Blood Institute, the National Cancer Institute and the Combat Casualty Care Research Program at the Department of Defense, was conducted in Bethesda MD on June 7–8, 2016. The workshop was structured into four sessions: (1) blood sciences; (2) exosome therapeutics; (3) next generation in vitro blood–brain barrier (BBB) models; and (4) BBB delivery and targeting. The first day of the workshop focused on the physiology of the blood and neuro-vascular unit, blood or biofluid-based molecular markers, extracellular vesicles associated with brain injury, and how these entities can be employed to better evaluate injury states and/or deliver therapeutics. The second day of the workshop focused on technical advances in in vitro models, BBB manipulations and nanoparticle-based drug carrier designs, with the goal of improving drug delivery to the central nervous system. The presentations and discussions underscored the role of the BBI in brain injury, as well as the role of the BBB as both a limiting factor and a potential conduit for drug delivery to the brain. At the conclusion of the meeting, the participants discussed challenges and opportunities confronting BBI translational researchers. In particular, the participants recommended using BBI translational research to stimulate advances in diagnostics, as well as targeted delivery approaches for detection and therapy of both brain injury and disease. Electronic supplementary material The online version of this article (doi:10.1186/s12987-017-0061-6) contains supplementary material, which is available to authorized users.

Extracellular α-synuclein is important in the pathogenesis of Parkinson's disease (PD) and also as a potential biomarker when tested in the cerebrospinal fluid (CSF). The performance of blood plasma or serum α-synuclein as a biomarker has been found to be inconsistent and generally ineffective, largely due to the contribution of peripherally derived α-synuclein. In this study, we discovered, via an intracerebroventricular injection of radiolabeled α-synuclein into mouse brain, that CSF α-synuclein was readily transported to blood, with a small portion being contained in exosomes that are relatively specific to the central nervous system (CNS). Consequently, we developed a technique to evaluate the levels of α-synuclein in these exosomes in individual plasma samples. When applied to a large cohort of clinical samples (267 PD, 215 controls), we found that in contrast to CSF α-synuclein concentrations, which are consistently reported to be lower in PD patients compared to controls, the levels of plasma exosomal α-synuclein were substantially higher in PD patients, suggesting an increased efflux of the protein to the peripheral blood of these patients. Furthermore, although no association was observed between plasma exosomal and CSF α-synuclein, a significant correlation between plasma exosomal α-synuclein and disease severity (r = 0.176, p = 0.004) was observed, and the diagnostic sensitivity and specificity achieved by plasma exosomal α-synuclein were comparable to those determined by CSF α-synuclein. Further studies are clearly needed to elucidate the mechanism involved in the transport of CNS α-synuclein to the periphery, which may lead to a more convenient and robust assessment of PD clinically.

Let \(\left\lfloor \cdot \right\rfloor \) be the floor function. In this paper, we show that for any fixed \(c\in \left( 1,\frac{77}{76}\right) \) there are infinitely many primes of the form \(p=\left\lfloor n^c\right\rfloor \), where \(n\) is a natural number with at most eight prime factors (counted with multiplicity).

Background: Disruption of the blood-brain barrier (BBB) occurs in many diseases and is often mediated by inflammatory and neuroimmune mechanisms. Inflammation is well established as a cause of BBB disruption, but many mechanistic questions remain. Methods: We used lipopolysaccharide (LPS) to induce inflammation and BBB disruption in mice. BBB disruption was measured using 14C-sucrose and radioactively labeled albumin. Brain cytokine responses were measured using multiplex technology and dependence on cyclooxygenase (COX) and oxidative stress determined by treatments with indomethacin and N-acetylcysteine. Astrocyte and microglia/macrophage responses were measured using brain immunohistochemistry. In vitro studies used Transwell cultures of primary brain endothelial cells co- or tri-cultured with astrocytes and pericytes to measure effects of LPS on transendothelial electrical resistance (TEER), cellular distribution of tight junction proteins, and permeability to 14C-sucrose and radioactive albumin. Results: In comparison to LPS-induced weight loss, the BBB was relatively resistant to LPS-induced disruption. Disruption occurred only with the highest dose of LPS and was most evident in the frontal cortex, thalamus, pons-medulla, and cerebellum with no disruption in the hypothalamus. The in vitro and in vivo patterns of LPS-induced disruption as measured with 14C-sucrose, radioactive albumin, and TEER suggested involvement of both paracellular and transcytotic pathways. Disruption as measured with albumin and 14C-sucrose, but not TEER, was blocked by indomethacin. N-acetylcysteine did not affect disruption. In vivo, the measures of neuroinflammation induced by LPS were mainly not reversed by indomethacin. In vitro, the effects on LPS and indomethacin were not altered when brain endothelial cells (BECs) were cultured with astrocytes or pericytes. Conclusions: The BBB is relatively resistant to LPS-induced disruption with some brain regions more vulnerable than others. LPS-induced disruption appears is to be dependent on COX but not on oxidative stress. Based on in vivo and in vitro measures of neuroinflammation, it appears that astrocytes, microglia/macrophages, and pericytes play little role in the LPS-mediated disruption of the BBB., Journal of Neuroinflammation, 12, 223; 2015

Let φ be the Euler function. Fix \({\ell\in{\mathbb N}}\) , and let \({{\fancyscript P}}\) be an arbitrary set of primes of positive lower natural density. Using a variant of the Alford–Granville–Pomerance construction, we show that there are infinitely many Carmichael numbers N with a totient of the form \({\varphi(N)=m^\ell \tilde m}\) , where \({m,\tilde m\in{\mathbb N}}\) and \({\tilde m}\) is a nonempty product of primes from the set \({{\fancyscript P}}\) . In particular, for any fixed natural number n, there are infinitely many Carmichael numbers N such that φ(N) = a2 + nb2 for some positive integers a and b.

We bound short sums of the form \({\sum_{n\le X}(\chi_1{*}\chi_2)(n)}\), where χ1*χ2 is the convolution of two primitive Dirichlet characters χ1 and χ2 with conductors q1 and q2, respectively.

We define Wieferich numbers to be those odd integers w≥3 that satisfy the congruence 2φ(w)≡1 (mod w2). It is clear that the distribution of Wieferich numbers is closely related to the distribution of Wieferich primes, and we give some quantitative forms of this statement. We establish several unconditional asymptotic results about Wieferich numbers; analogous results for the set of Wieferich primes remain out of reach. Finally, we consider several modifications of the above definition and demonstrate that our methods apply to such sets of integers as well.

In this note, we show that the number of composite integers n ≤ x such that ϕ(n)|n − 1 is at most O(x 1/2(log log x)1/2), thus improving earlier results by Pomerance and by Shan.

We establish upper bounds for multiplicative character sums with the function σg (n) which computes the sum of the digits of n in a fixed base g ≥ 2. Our results may be viewed as analogues of some previously known results for exponential sums with sum of g-ary digits function.

Let ϕ and λ be the Euler and Carmichael functions, respectively. In this paper, we establish lower and upper bounds for the number of positive integers n ≤ x such that ϕ(λ(n)) = λ(ϕ(n)). We also study the normal order of the function ϕ(λ(n))/λ(ϕ(n)).

In this paper, we study some divisibility properties of palindromic numbers in a fixed base ]]> ]]> ]]> ]]> ]]> ]]> ]]> ]]> g\ge 2$. In particular, if ${\mathcal P}_L$ denotes the set of palindromes with precisely $L$ digits, we show that for any sufficiently large value of $L$ there exists a palindrome $n\in{\mathcal P}_L$ with at least $(\log\log n)^{1+o(1)}$ distinct prime divisors, and there exists a palindrome $n\in{\mathcal P}_L$ with a prime factor of size at least $(\log n)^{2+o(1)}$.

We study formal power series whose coefficients are taken to be a variety of number theoretic functions, such as the Euler, Mobius and divisor functions. We show that these power series are irrational over ℤ[X], and we obtain lower bounds on the precision of their rational approximations.

Let ϕ(n) and λ(n) denote the Euler and Carmichael functions, respectively. In this paper, we investigate the equation ϕ(n)r = λ(n)s, where r ≥ s ≥ 1 are fixed positive integers. We also study those positive integers n, not equal to a prime or twice a prime, such that ϕ(n) = p − 1 holds with some prime p, as well as those positive integers n such that the equation ϕ(n) = f(m) holds with some integer m, where f is a fixed polynomial with integer coefficients and degree degf > 1.

Although the prognostic significance of depression and hostility has been established, little is known about how they operate together to influence disease processes. This study explored the independent and interactive relationships between these constructs and the expression of inflammatory markers implicated in the pathogenesis of coronary heart disease. One hundred adults completed measures of cynical hostility and depressive symptoms, and had blood drawn to assess serum levels of interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha. Depression was directly related to inflammatory markers, but hostility was not. A significant interaction between hostility and depression emerged. Among participants scoring low in depressive symptoms, hostility was positively associated with interleukin-6 and tumor necrosis factor-alpha concentrations. Hostility's association with these inflammatory markers was much weaker among participants with moderate depressive symptoms, however, and virtually nil among participants with severe depressive symptoms. Neither depression nor hostility was associated with interleukin-1 beta concentrations. These findings highlight the importance of considering both the independent and interactive relationships among psychosocial characteristics involved in disease.

In this paper, we use elementary methods to derive some new identities for special values of the Riemann zeta function.

Over the last ten years, the application of high frequency dielectric techniques for the assessment of adhesively bonded structures has been investigated. The technique has been used for the study of adhesively bonded aluminium structures and its application to carbon fibre reinforced plastic (CFRP) bonded structures forms the basis of this paper. The electrical conductivity of the carbon fibres in the CFRP composite materials is sufficiently high for adhesively bonded structures to exhibit the properties of a wave-guide. The non-conductive adhesive behaves as a dielectric. The time domain data allows the integrity of the structure to be explored and is sensitive to the orientation of the fibres at the adherent-adhesive interface. Furthermore, a good correlation is shown between time domain dielectric spectroscopy and gravimetric results. This study indicates that the success obtained in the application of high frequency dielectric measurements to adhesively bonded aluminium structures is also applicable to CFRP bonded structures. The dielectric studies not only indicate a new way to assess the state of such a structure but also are producing new insight into the application of dielectric time domain response (TDR) measurement to non-isotropic materials.

Background P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) play a critical role in keeping neurotoxic substances from entering the brain. We and others have previously reported an impact of inflammation on the regulation of adult blood–brain barrier (BBB) efflux transporters. However, studies in children have not been done. From the pediatric clinical perspective, it is important to understand how the central nervous system (CNS) and BBB drug efflux transporters differ in childhood from those of adults under normal and inflammatory conditions. Therefore, we examined and compared the regulation of P-gp and BCRP expression and transport activity in young and adult BBB and investigated the molecular mechanisms underlying inflammatory responses. Methods Rats at postnatal day (P) P21 and P84, corresponding to the juvenile and adult stages of human brain maturation, respectively, were treated with endothelin-1 (ET-1) given by the intracerebroventricular (icv) route. Twenty-four hours later, we measured P-gp and BCRP protein expression in isolated brain capillary by immunoblotting as well as by transport activity in vivo by measuring the unbound drug partitioning coefficient of the brain (Kp,uu,brain) of known efflux transporter substrates administered intravenously. Glial activation was measured by immunohistochemistry. The release of cytokines/chemokines (interleukins-1α, 1-β (IL-1β), -6 (IL-6), -10 (IL-10), monocyte chemoattractant protein (MCP-1/CCL2), fractalkine and tissue inhibitor of metalloproteinases-1 (TIMP-1)) were simultaneously measured in brain and serum samples using the Agilent Technology cytokine microarray. Results We found that juvenile and adult BBBs exhibited similar P-gp and BCRP transport activities in the normal physiological conditions. However, long-term exposure of the juvenile brain to low-dose of ET-1 did not change BBB P-gp transport activity but tended to decrease BCRP transport activity in the juvenile brain, while a significant increase of the activity of both transporters was evidenced at the BBB in the adult brain. Moreover, juvenile and adult brain showed differences in their expression profiles of cytokines and chemokines mediated by ET-1. Conclusions BBB transporter activity during neuroinflammation differs between the juvenile and adult brains. These findings emphasize the importance of considering differential P-gp and BCRP transport regulation mechanisms between adult and juvenile BBB in the context of neuroinflammation.

Background Immune cell trafficking into the CNS and other tissues plays important roles in health and disease. Rapid quantitative methods are not available that could be used to study many of the dynamic aspects of immune cell-tissue interactions. Methods We used pharmacokinetics and modeling to quantify and characterize the trafficking of radioactively labeled lymphocytes into brain and peripheral tissues. We used variance from two-way ANOVAs with 2 × 2 experimental designs to model the relative influences of lymphocytes and target tissues in trafficking. Results We found that in male CD-1 mice, about 1 in 5,000 intravenously injected lymphocytes entered each gram of brain. Uptake by brain was 2 to 3 times higher in naïve SJL females, but uptake by spleen and clearance from blood was lower, demonstrating a dichotomy in immune cell distribution. Treatment of CD-1 mice with lipopolysaccharide (LPS) increased immune cell uptake into brain but decreased uptake by spleen and axillary nodes. Conclusions Differences in brain uptake and in uptake by spleen between SJL and CD-1 mice were primarily determined by lymphocytes, whereas differences in uptake with LPS were primarily determined by lymphocytes for the brain but by the tissues for the spleen and the axillary lymph node. These results show that immune cells normally enter the CNS and that tissues and immune cells interact in ways that can be quantified by pharmacokinetic models.

Peptides have been shown to cross the blood–brain barrier (BBB) as intact molecules so that they can influence the central nervous system. Peptides cross by saturable and nonsaturable mechanisms in the direction of both brain to blood and blood to brain. Passage of peptides, especially by saturable transport, has been shown to be influenced by pharmacological agents and physiological events. These findings support the view that peptides or their analogues could be useful as therapeutic agents for disorders of the central nervous system. They also suggest strategies in approaching therapeutic goals, including manipulating transport rates, targeting diseases due to altered BBB–peptide interactions, and designing analogues capable of taking advantage of such mechanisms of passage as paracellular trans-membrane diffusion and brain-to-blood transport.

Amyloid beta protein (A[beta]) is well recognized as having a significant role in the pathogenesis of Alzheimer's disease (AD). The reason for the presence of A[beta] and its physiological role in non-disease states is not clear. In these studies, low doses of A[beta] enhanced memory retention in two memory tasks and enhanced acetylcholine production in the hippocampus in vivo. We then tested whether endogenous A[beta] has a role in learning and memory in young, cognitively intact mice by blocking endogenous A[beta] in healthy 2-month-old CD-1 mice. Blocking A[beta] with antibody to A[beta] or DFFVG (which blocks A[beta] binding) or decreasing A[beta] expression with an antisense directed at the A[beta] precursor APP all resulted in impaired learning in T-maze foot-shock avoidance. Finally, A[beta]1-42 facilitated induction and maintenance of long term potentiation in hippocampal slices, whereas antibodies to A[beta] inhibited hippocampal LTP. These results indicate that in normal healthy young animals the presence of A[beta] is important for learning and memory.

In two experiments, we used lateralized versions of the comparative judgment paradigm to investigate the effects of semantic congruity on hemispheric processing of symbolic information. When the comparative adjectives used in instructions were congruent with the scale end from which stimulus terms were drawn, reaction times were shorter when the hemisphere to which the terms were lateralized also controlled the hand used to register the response than when instructions and stimuli were semantically incongruent. These laterality-effect patterns suggest that hemispheric cooperation increases processing efficiency.

The first experiment reported here shows that cuing subjects about the identity of items in advance of a visual display has approximately the same effect on attentional selection (as measured by costs and benefits in reaction time) as cuing the location at which they will appear. The second experiment shows that the “spotlight” of directed spatial attention can be content-specific so that it facilitates perception of some items more than others. Both of these findings challenge the spotlight metaphor of attention by which spatial selection is assumed to precede processing for item identity and in which the spotlight itself is content-neutral. Two alternate hypotheses are proposed.

Over the last ten years, the application of high frequency dielectric spectroscopy techniques for the assessment of composite structures has been investigated. Novel approaches to assess non-destructively the evolution during ageing of adhesively bonded carbon fibre reinforced plastic (CFRP) structures and bulk glass fibre reinforced plastic (GRP) structures are presented in this paper and the results are critically assessed.The applicability and limitations of dielectric measurements, in both frequency and time domain, to the monitoring of water ingress at 30°C and 60°C are examined. The correlation between gravimetric and high frequency dielectric spectroscopy data demonstrates the suitability of the techniques regarding the assessment of water uptake in composites structures and illustrates its potential as a non-destructive evaluation (NDE) technique. The dielectric time domain response (TDR) study of adhesively bonded structures indicates a new way to assess such structures. The approach for frequency domain analysis of bulk GRP using a coaxial probe technique indicates the potential portability of the technique for in-situ measurements.

Dielectric techniques have the potential of allowing observation of changes in the dipole mobility within an adhesive joint structure as a result of its exposure to a warm humid environment. Water molecules absorbed by an adhesive resin will exhibit a series of distinct relaxation features, which are characteristic of the environment in which the molecules are located. Hydration of the surface oxide of an aluminium-epoxy joint will produce a distinctive dielectric relaxation at approximately 1 MHz which is quantitatively related to the amount of hydroxide formed. Data on aged adhesive joints indicates that the dielectric technique has potential for the study of the changes occurring within the joints and the technique may be also used for studies of carbon fibre - epoxy - carbon fibre structures.

Substances cross the blood-brain barrier (BBB) by a variety of mechanisms. These include transmembrane diffusion, saturable transporters, adsorptive endocytosis, and the extracellular pathways. Here, we focus on the chief characteristics of two mechanisms especially important in drug delivery: transmembrane diffusion and transporters. Transmembrane diffusion is non-saturable and depends, on first analysis, on the physicochemical characteristics of the substance. However, brain-to-blood efflux systems, enzymatic activity, plasma protein binding, and cerebral blood flow can greatly alter the amount of the substance crossing the BBB. Transport systems increase uptake of ligands by roughly 10-fold and are modified by physiological events and disease states. Most drugs in clinical use to date are small, lipid soluble molecules that cross the BBB by transmembrane diffusion. However, many drug delivery strategies in development target peptides, regulatory proteins, oligonucleotides, glycoproteins, and enzymes for which transporters have been described in recent years. We discuss two examples of drug delivery for newly discovered transporters: that for phosphorothioate oligonucleotides and for enzymes.

This article describes a laboratory computer system that uses a PDP-11/10 CPU and a graphics processor to simulate a multifield tachistoscope and to run a great number of psychological experiments. The potential of the hardware is discussed, and two useful programs are presented.

This note is prompted in part by the unsettling report of Mollon and Polden (1978) on the time constants of tachistoscopes. They tested a number of tachistoscopes, including an Iconix fitted with the lamps used by Banks and Barber (1977), and found that they typically required about 18 msec to reach 900/0 of full output when they were turned on or to decline to 10% of output when turned off. Furthermore, the spectral composition of the light changed Over the rise and fall periods. The change in spectral composition is particularly important because the conclusion we drew (Banks & Barber, 1977), that iconic memory was not strictly a rod phenomenon, depended in part on use of stimuli that present zero contrast to the rods, despite being clearly distinguishable to the cones. In that research we created letter arrays by using one color of paper for figure and another for ground such that the cones, but not the rods, could see the contrast between the colors and thus only the cones could be used to detect the letters. The fact that these arrays gave typical iconic decay curves and a partial report superiority seemed to us to be good evidence that iconic memory did not require the rods. We realized, of course, that the matching of the colored papers depends on the spectral composition of the illuminant, and we made our matches using as an illuminant the steady-state light of the stimulus field of the Iconix, filtered through the two mirrors through which the stimulus was seen in Our experiments. If, however, the spectral composition of the light during the rise and fall periods of the tachistoscope lamps was not the same as it was during the steady-state period, then the stimulus arrays would not have zero contrast for the rods during these periods, and the rods might have been able to mediate iconic memory during experimental trials. Another motivation for this note comes from Sakitt and Long (1979), which shows that a small

The effect of aluminum on levels of inorganic phosphorus and acetylcholinesterase in blood and brain and on permeability of the blood-brain barrier (BBB) in different regions of the brain to the neuropeptide delta-sleep-inducing peptide (DSIP) was studied in adult rats. Aluminum (100 mg/kg) significantly increased the permeability of the BBB to intracarotid 125I-N-Tyr-DSIP so that levels of radioactivity in whole brain were 45% higher than in control animals. The pattern of regional distribution of radioactivity in the brain was, however, unaffected, demonstrating that the affect of aluminum occurs throughout the BBB. Aluminum also significantly decreased inorganic phosphorus levels in the serum by 19%, but this effect did not correlate with BBB permeability to DSIP. Aluminum did not decrease brain levels of phosphorus despite the drop in blood levels of phosphorus nor affect brain or blood levels of acetylcholinesterase. Experiments with radioactive 32P reinforced the finding that blood but not brain levels of phosphorus are reliably affected by aluminum. The lack of correlation between changes in BBB permeability and decreased levels of inorganic phosphorus in the blood suggests that the effect of aluminum may not be mediated by its effects on phosphorus metabolism. Also, the change in BBB permeability after administration of aluminum does not appear to depend on changes in brain cholinergic activity but does occur throughout the brain.

This research studies lateral interference among items in the visual field under conditions in which central cognitive factors such as attention and memory limitations are eliminated or controlled for. Under these conditions lateral masking is still found, and it is still asymmetrical (peripheral items interfere with recognition of central items more than central with peripheral). These experiments therefore add to the evidence that both lateral interference and the asymmetry of interference have a component that does not result from cognitive strategies. The experiments also add to the evidence that the asymmetry effect at the sensory level can be attributed to the falloff in acuity from the center to the periphery of the retina, since the mean eccentricity of the target-mask cluster is more peripheral with a peripheral mask than with a central mask. The hypothesis is advanced that the asymmetry effect, as well as lateral interference itself, at the sensory level results from the grouping of target and mask into a single Gestalt-like configuration. The final experiment in the series supports this hypothesis

This research compares the time required for perceptual discriminations among pairs of physically present objects (circles) with the time required to discriminate pairs of symbols Inonsense syllables) that subjects learned to associate uniquely with each of the circles. Four experiments show very large differences between symbolic and perceptual discriminations. Discrimination times for the perceptual stimuli declined systematically as their size ratio increased, but discriminations among the associated nonsense syllables showed only a strictly ordinal effect of position in the series. Discriminations among the symbolic stimuli showed a large semantic congruity effect, but the perceptual stimuli showed none. The research does not replicate previous results showing similarities between perceptual and symbolic processing suggestive of image processing. We conclude that in the symbolic task subjects use only ordinal information rather than images or analog representations of the associated circles. We propose that perceptual discriminations show a semantic congruity effect only when they are processed as if the perceptual stimuli were symbolic.

This study shows that the subjective sense of intoxication produced by ethyl alcohol exhibits classical sensory adaptation. The subjects reported a degree of intoxication that increased with the level of blood alcohol at the time of the report. However, a given level of blood alcohol produced less intoxication when it followed a high blood alcohol level than when it followed a low one. This effect of a prior level of blood alcohol on the effect of a present one implies that the mechanism that mediates alcohol intoxication adapts much as do exteroceptive sensory systems. Data on one chronic alcoholic suggest that alcohol abusers may adapt more rapidly than nonabusers.

This research uses comparative judgments of the relative loudness of sounds to make a critical test of one theory of the mental representation of continuous physical attributes. The first two experiments find a semantic congruity effect, which is an interaction such that subjects can pick the louder of two loud sounds faster than the softer, and the softer of two quiet sounds faster than the louder. According to the theory under test, physical quantities are stored as points on a representational continuum, with a variance as well as a mean placement on it. The theory predicts the semantic congruity effect by assuming that the variance of placement of intensities on the representational continuum is a function of the direction of judgment: a soft sound will have less variance than a loud one when judged for softness and more when judged for loudness. Since the speed of making a judgment increases as variance decreases, the theory predicts a semantic congruity effect. However, for loudness, it can be shown that variance does not change in the manner assumed. The finding of a semantic congruity effect therefore disconfirms the theory. Alternative models are discussed. This research was supported by NSF Grant BNS 78-17442.

The present research tests limited- and unlimited-capacity theories of perception by comparing accuracy in detection and search tasks under conditions of simultaneous and successive presentation of array items. The unlimited-capacity approach predicts no difference between simultaneous and successive presentation when nonperceptual factors are controlled. The limitedcapacity approach predicts an advantage for successive presentation when the number of simultaneously presented items exceeds processing capacity. In five experiments using a consistent mapping paradigm, successive presentation was reliably better than simultaneous presentation.

The way in which the apparent magnitude of numbers grows with their absolute magnitude was measured with a modified version of the direct technique Marks and Slawson (1966) used to determine the psychophysical exponent for loudness. This modified technique required subjects to estimate how evenly and randomly a sequence of integers appeared to sample the numerical continuum. The results indicate that the apparent magnitude of numbers increases with a decelerated power function of their arithmetic magnitude when a series samples from an open-ended range. However, when an upper boundary of the range is specified, the subjective scale seems to be linear. Random productions of numbers parallel the results found with judgments of presented sequences. The two scales of number provide the basis for an interpretation of the difference between magnitude and category scales: that subjects use numbers differently when the response scale is open-ended Imagnitude estimation than when it has a fixed upper limit tcategory scale. Given the assumption that subjects use numbers in this way in the two tasks, the qualitative relation between magnitude and category scales is predicted.