An integrated self-optimizing programmable chemical synthesis and reaction engine.

Robotic platforms for chemistry are developing rapidly but most systems are not currently able to adapt to changing circumstances in real-time. We present a dynamically programmable system capable of making, optimizing, and discovering new molecules which utilizes seven sensors that continuously monitor the reaction. By developing a dynamic programming language, we demonstrate the 10-fold scale-up of a highly exothermic oxidation reaction, end point detection, as well as detecting critical hardware failures. We also show how the use of in-line spectroscopy such as HPLC, Raman, and NMR can be used for closed-loop optimization of reactions, exemplified using Van Leusen oxazole synthesis, a four-component Ugi condensation and manganese-catalysed epoxidation reactions, as well as two previously unreported reactions, discovered from a selected chemical space, providing up to 50% yield improvement over 25-50 iterations. Finally, we demonstrate an experimental pipeline to explore a trifluoromethylations reaction space, that discovers new molecules.

Next-generation MRI scanner designed for ultra-high-resolution human brain imaging at 7 Tesla.

To increase granularity in human neuroimaging science, we designed and built a next-generation 7 Tesla magnetic resonance imaging scanner to reach ultra-high resolution by implementing several advances in hardware. To improve spatial encoding and increase the image signal-to-noise ratio, we developed a head-only asymmetric gradient coil (200 mT m-1, 900 T m-1s-1) with an additional third layer of windings. We integrated a 128-channel receiver system with 64- and 96-channel receiver coil arrays to boost signal in the cerebral cortex while reducing g-factor noise to enable higher accelerations. A 16-channel transmit system reduced power deposition and improved image uniformity. The scanner routinely performs functional imaging studies at 0.35-0.45 mm isotropic spatial resolution to reveal cortical layer functional activity, achieves high angular resolution in diffusion imaging and reduces acquisition time for both functional and structural imaging.

A 128-channel receive array for cortical brain imaging at 7 T.

PURPOSE: A 128-channel receive-only array for brain imaging at 7 T was simulated, designed, constructed, and tested within a high-performance head gradient designed for high-resolution functional imaging. METHODS: The coil used a tight-fitting helmet geometry populated with 128 loop elements and preamplifiers to fit into a 39 cm diameter space inside a built-in gradient. The signal-to-noise ratio (SNR) and parallel imaging performance (1/g) were measured in vivo and simulated using electromagnetic modeling. The histogram of 1/g factors was analyzed to assess the range of performance. The array's performance was compared to the industry-standard 32-channel receive array and a 64-channel research array. RESULTS: It was possible to construct the 128-channel array with body noise-dominated loops producing an average noise correlation of 5.4%. Measurements showed increased sensitivity compared with the 32-channel and 64-channel array through a combination of higher intrinsic SNR and g-factor improvements. For unaccelerated imaging, the 128-channel array showed SNR gains of 17.6% and 9.3% compared to the 32-channel and 64-channel array, respectively, at the center of the brain and 42% and 18% higher SNR in the peripheral brain regions including the cortex. For R = 5 accelerated imaging, these gains were 44.2% and 24.3% at the brain center and 86.7% and 48.7% in the cortex. The 1/g-factor histograms show both an improved mean and a tighter distribution by increasing the channel count, with both effects becoming more pronounced at higher accelerations. CONCLUSION: The experimental results confirm that increasing the channel count to 128 channels is beneficial for 7T brain imaging, both for increasing SNR in peripheral brain regions and for accelerated imaging.

Self-expanding intestinal expansion sleeves (IES) for short gut syndrome.

PURPOSE: Many disease processes (necrotizing enterocolitis, caustic esophageal injury, malrotation with volvulus), can result in short-gut syndrome (SGS), where remnant intestinal segments may dilate axially, but rarely elongate longitudinally. Here we mechanically characterize a novel model of a self-expanding mesh prototype intestinal expanding sleeve (IES) for use in SGS. METHODS: Gut lengthening was achieved using a proprietary cylindrical layered polyethylene terephthalate IES device with helicoid trusses with isometric ends. The IES is pre-contracted by diametric expansion, deployed into the gut and anchored with bioabsorbable sutures. IES expansion to its equilibrium dimension maintained longitudinal gut tension, which may permit remodeling, increased absorptive surface area while preserving vascular and nervous supplies. We performed mechanical testing to obtain the effective force-displacement characterization achieved on these prototypes and evaluated minimal numbers of sutures needed for its anchoring. Furthermore, we deployed these devices in small and large intestines of New Zealand White rabbits, measured IES length-tension relationships and measured post-implant gut expansion ex vivo. Histology of the gut before and after implantation was also evaluated. RESULTS: Longitudinal tension using IES did not result in suture failure. Maximum IES suture mechanical loading was tested using 4-6 sutures; we found similar failure loads of 2.95 ± 0.64, 4 ± 1.9 and 3.16 ± 0.24 Newtons for 4, 6 and 8 sutures, respectively (n = 3, n.s). Pre-contracted IES tubes were deployed at 67 ± 4% of initial length (i.l.); in the large bowel these expanded significantly to 81.5 ± 3.7% of i.l. (p = 0.014, n = 4). In the small bowel, pre-contracted IES were 61 ± 3.8% of i.l.; these expanded significantly to 82.7 ± 7.4% of i.l. (p = 0.0009, n = 6). This resulted in an immediate 24 ± 7.8% and 36.2 ± 11% increase in gut length when deployed in large and small bowels, respectively, with maintained longitudinal tension. Maintained IES induced tension produced gut wall thinning; gut histopathological evaluation is currently under evaluation. CONCLUSION: IES is a versatile platform for gaining length in SGS, which may be simply deployed via feeding tubes. Our results need further validation for biocompatibility and mechanical characterization to optimize use in gut expansion.

Chemputation and the Standardization of Chemical Informatics.

The explosion in the use of machine learning for automated chemical reaction optimization is gathering pace. However, the lack of a standard architecture that connects the concept of chemical transformations universally to software and hardware provides a barrier to using the results of these optimizations and could cause the loss of relevant data and prevent reactions from being reproducible or unexpected findings verifiable or explainable. In this Perspective, we describe how the development of the field of digital chemistry or chemputation, that is the universal code-enabled control of chemical reactions using a standard language and ontology, will remove these barriers allowing users to focus on the chemistry and plug in algorithms according to the problem space to be explored or unit function to be optimized. We describe a standard hardware (the chemical processing programming architecture-the ChemPU) to encompass all chemical synthesis, an approach which unifies all chemistry automation strategies, from solid-phase peptide synthesis, to HTE flow chemistry platforms, while at the same time establishing a publication standard so that researchers can exchange chemical code (χDL) to ensure reproducibility and interoperability. Not only can a vast range of different chemistries be plugged into the hardware, but the ever-expanding developments in software and algorithms can also be accommodated. These technologies, when combined will allow chemistry, or chemputation, to follow computation-that is the running of code across many different types of capable hardware to get the same result every time with a low error rate.

Convergence of multiple synthetic paradigms in a universally programmable chemical synthesis machine.

Although the automatic synthesis of molecules has been established, each reaction class uses bespoke hardware. This means that the connection of multi-step syntheses in a single machine to run many different protocols and reactions is not possible, as manual intervention is required. Here we show how the Chemputer synthesis robot can be programmed to perform many different reactions, including solid-phase peptide synthesis, iterative cross-coupling and accessing reactive, unstable diazirines in a single, unified system with high yields and purity. Developing universal and modular hardware that can be automated using one software system makes a wide variety of batch chemistry accessible. This is shown by our system, which performed around 8,500 operations while reusing only 22 distinct steps in 10 unique modules, with the code able to access 17 different reactions. We also demonstrate a complex convergent robotic synthesis of a peptide reacted with a diazirine-a process requiring 12 synthetic steps.

Comparison of BOLD and CBV using 3D EPI and 3D GRASE for cortical layer functional MRI at 7 T.

PURPOSE: Functional MRI (fMRI) at the mesoscale of cortical layers and columns requires both sensitivity and specificity, the latter of which can be compromised if the imaging method is affected by vascular artifacts, particularly cortical draining veins at the pial surface. Recent studies have shown that cerebral blood volume (CBV) imaging is more specific to the actual laminar locus of neural activity than BOLD imaging using standard gradient-echo EPI sequences. Gradient and spin-echo (GRASE) BOLD imaging has also shown greater specificity when compared with standard gradient-echo EPI BOLD. Here we directly compare CBV and BOLD contrasts in high-resolution imaging of the primary motor cortex for laminar functional MRI in four combinations of signal labeling, CBV using slice-selective slab-inversion vascular space occupancy (VASO) and BOLD, each with 3D gradient-echo EPI and zoomed 3D-GRASE image readouts. METHODS: Activations were measured using each sequence and contrast combination during a motor task. Activation profiles across cortical depth were measured to assess the sensitivity and specificity (pial bias) of each method. RESULTS: Both CBV imaging using gradient-echo 3D-EPI and BOLD imaging using 3D-GRASE show similar specificity and sensitivity and are therefore useful tools for mesoscopic functional MRI in the human cortex. The combination of GRASE and VASO did not demonstrate high levels of sensitivity, nor show increased specificity. CONCLUSION: Three-dimensional EPI with VASO contrast and 3D-GRASE with BOLD contrast both demonstrate sufficient sensitivity and specificity for laminar functional MRI to be used by neuroscientists in a wide range of investigations of depth-dependent neural circuitry in the human brain.

Dynamic gut microbiome changes following regional intestinal lymphatic obstruction in primates.

The pathogenesis of inflammatory bowel disease (IBD) has been linked with lymphostasis, but whether and how lymphatic obstruction might disturb the intestinal microbiome in the setting of Crohn's Disease (CD) is currently unknown. We employed a new model of CD in African Green monkeys, termed 'ATLAS' (African green monkey truncation of lymphatics with obstruction and sclerosis), to evaluate how gut lymphatic obstruction alters the intestinal microbiome at 7, 21 and 61 days. Remarkable changes in several microbial sub- groupings within the gut microbiome were observed at 7 days post-ATLAS compared to controls including increased abundance of Prevotellaceae and Bacteroidetes-Prevotella-Porphyromonas (BPP), which may contribute to disease activity in this model of gut injury. To the best of our knowledge, these findings represent the first report linking lymphatic structural/gut functional changes with alterations in the gut microbiome as they may relate to the pathophysiology of CD.

Neurolymphatic biomarkers of brain endothelial inflammatory activation: Implications for multiple sclerosis diagnosis.

AIMS: Multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in young adults, and its diagnosis is often delayed due to the lack of diagnostic markers. Initiation of disease -modifying therapy in the early stages of MS is especially critical because currently available therapy mostly target relapsing-remitting MS, and is less effective as disease progresses into the more chronic form of secondary-progressive MS. Therefore, exploring specific and sensitive biomarkers will facilitate an expedited and more accurate diagnosis to allow currently available therapies to be more effective. MAIN METHODS: Western blotting was conducted to detect the expression of neurolymphatic proteins in human brain endothelial cells in culture. Additionally, using a cohort of 150 patients with relapsing remitting MS, 26 with secondary progressive MS, and 60 healthy control samples, neurolymphatic protein expression was detected in serum samples using dot blot analysis. KEY FINDINGS: Human brain microvascular endothelial cells express neurolymphatic markers. Neurolymphatic protein abundance increases with tumor necrosis factor (TNF)-α stimulation but decreases with interferon (IFN)- γ or combined (TNF + IFN) treatment. Circulating neurolymphatic protein levels is significantly lower in MS patients. Further, one of the markers, FOXC2, is associated with the clinical stages of MS, with significantly lower expression in secondary progressive MS compared to relapsing remitting MS. SIGNIFICANCE: Our findings describe brain endothelial expression of neurolymphatic proteins, which is altered under inflammatory stress, and provide a possibility of using a collective pool of circulating neurolymphatic proteins as a diagnostic and prognostic biomarker of MS.

Venous thromboembolism in IBD: Increased risk for women in CD?

Although coagulation disturbances have been described in inflammatory bowel disease (IBD), it remains unclear how common venous thromboembolism (VTE) is in IBD, and what factors influence VTE frequency. We evaluated VTE in Crohn's disease (CD) and ulcerative colitis (UC) at LSUHSC-S, a southern US medical center with an approximately equal White: African-American (AA) (1.12:1) patient base. This retrospective study evaluated VTE as a co-morbidity in IBD as a function of age, gender and race based on ICD-10 coding (2011-2015.) Results. Of 276 IBD diagnostic records, 213 were for CD (77.17%) and 63 for UC (22.8%). 52% of the CD patients were white, 42% were AA, and 6% were other. 42% of CD patients were male, with 58% were female. 6.1% (13 patients) of the 213 CD patients had a VTE. Of these 13 CD patients, 9 had active disease and 4 were in remission. 9 of 13 were female and 4 were male, with 5 white patients and 4 A A patients. 63 patients were diagnosed with UC, 3.38-fold fewer cases than CD. 25 UC patients were white, 25 were AA and 13 were in other ethnic groups. Of 63 UC cases, 2 UC patients had a VTE, both with active disease. At our institution, VTE appears to be 3x more frequently associated with CD than UC and was more common in white female patients. The recognition of VTE risk in CD, particularly in women, may be an important observation which may guide therapy and limit potentially life-threatening consequences.

Potential therapeutic roles of stem cells in ischemia-reperfusion injury.

Ischemia-reperfusion injury (I/RI), produced by an initial interruption of organ blood flow and its subsequent restoration, contributes significantly to the pathophysiologies of stroke, myocardial infarction, renal I/RI, intestinal I/RI and liver I/RI, which are major causes of disability (including transplant failure) and even mortality. While the restoration of blood flow is required to restore oxygen and nutrient requirements, reperfusion often triggers local and systemic inflammatory responses and subsequently elevate the ischemic insult where the duration of ischemia determines the magnitude of I/RI damage. I/RI increases vascular leakage, changes transcriptional and cell death programs, drives leukocyte entrapment and inflammation and oxidative stress in tissues. Therapeutic approaches which reduce complications associated with I/RI are desperately needed to address the clinical and economic burden created by I/RI. Stem cells (SC) represent ubiquitous and uncommitted cell populations with the ability to self-renew and differentiate into one or more developmental 'fates'. Like immune cells, stem cells can home to and penetrate I/R-injured tissues, where they can differentiate into target tissues and induce trophic paracrine signaling which suppress injury and maintain tissue functions perturbed by ischemia-reperfusion. This review article summarizes the present use and possible protective mechanisms underlying stem cell protection in diverse forms of ischemia-reperfusion.

Hydrogen sulfide: Therapeutic or injurious in ischemic stroke?

Hydrogen sulfide (H2S) has been identified as a vasodilatory, neuromodulatory, and anti-inflammatory gasotransmitter with antioxidant properties. Studies focused in cardiac tissue suggest H2S functions as a protective agent; however in the central nervous system (CNS) the effects of H2S during states of stress or injury, such as stroke, remain controversial. Currently, the application of H2S donors and modulators in stroke depends on the type of H2S donor and the timing of the therapy.

Liver Cholestasis Secondary to Syphilis in an Immunocompetent Patient.

Liver involvement is a known feature of secondary syphilis. The prevalence of hepatitis in secondary syphilis ranges broadly from 1 to 50%. We report a case of a 37-year-old man with type 1 diabetes mellitus and sickle cell trait presenting with jaundice and acute liver cholestasis. Abdominal ultrasound revealed mild hepatic fatty infiltration. RPR and Treponema pallidum IgG results were positive with a reflex titer of 1:64. Liver biopsy revealed chronic hepatitis with normal hepatic architecture, Kupffer cell hyperplasia, hepatic cholestasis, and ductal proliferation suggestive of syphilitic hepatitis.

Characterising Wildlife Trade Market Supply-Demand Dynamics.

The trade in wildlife products can represent an important source of income for poor people, but also threaten wildlife locally, regionally and internationally. Bushmeat provides livelihoods for hunters, traders and sellers, protein to rural and urban consumers, and has depleted the populations of many tropical forest species. Management interventions can be targeted towards the consumers or suppliers of wildlife products. There has been a general assumption in the bushmeat literature that the urban trade is driven by consumer demand with hunters simply fulfilling this demand. Using the urban bushmeat trade in the city of Kumasi, Ghana, as a case study, we use a range of datasets to explore the processes driving the urban bushmeat trade. We characterise the nature of supply and demand by explicitly considering three market attributes: resource condition, hunter behaviour, and consumer behaviour. Our results suggest that bushmeat resources around Kumasi are becoming increasingly depleted and are unable to meet demand, that hunters move in and out of the trade independently of price signals generated by the market, and that, for the Kumasi bushmeat system, consumption levels are driven not by consumer choice but by shortfalls in supply and consequent price responses. Together, these results indicate that supply-side processes dominate the urban bushmeat trade in Kumasi. This suggests that future management interventions should focus on changing hunter behaviour, although complementary interventions targeting consumer demand are also likely to be necessary in the long term. Our approach represents a structured and repeatable method to assessing market dynamics in information-poor systems. The findings serve as a caution against assuming that wildlife markets are demand driven, and highlight the value of characterising market dynamics to inform appropriate management.

TGF-ß1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis.

Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial-mesenchymal transition (EMT) in response to transforming growth factor-ß (TGF-ß1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-ß1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-ß1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-ß1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-ß1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells.

Blood circulating microparticle species in relapsing-remitting and secondary progressive multiple sclerosis. A case-control, cross sectional study with conventional MRI and advanced iron content imaging outcomes.

BACKGROUND: Although multiple sclerosis (MS) is thought to represent an excessive and inappropriate immune response to several central nervous system (CNS) autoantigens, increasing evidence also suggests that MS may also be a neurovascular inflammatory disease, characterized by endothelial activation and shedding of cell membrane microdomains known as 'microparticles' into the circulation. OBJECTIVE: To investigate the relationships between these endothelial biomarkers and MS. METHODS: We examined the relative abundance of CD31(+)/PECAM-1, CD51(+)CD61(+) (αV-ß3) and CD54(+) (ICAM-1) bearing microparticles in sera of healthy individuals, patients with relapsing-remitting MS, and secondary-progressive MS. We also investigated the correlation among circulating levels of different microparticle species in MS with conventional MRI (T2- and T1-lesion volumes and brain atrophy), as well as novel MR modalities [assessment of iron content on susceptibility-weighted imaging (SWI)-filtered phase]. RESULTS: Differences in circulating microparticle levels were found among MS groups, and several microparticle species (CD31(+)/CD51(+)/CD61(+)/CD54(+)) were found to correlate with conventional MRI and SWI features of MS. CONCLUSION: These results indicate that circulating microparticles' profiles in MS may support mechanistic roles for microvascular stress and injury which is an underlying contributor not only to MS initiation and progression, but also to pro-inflammatory responses.

Number and location of drainage catheter side holes: in vitro evaluation.

AIM: To evaluate the influence of number and location of catheter shaft side holes regarding drainage efficiency in an in vitro model. MATERIALS AND METHODS: Three different drainage catheter models were constructed: open-ended model with no side holes (one catheter), unilateral side hole model (six catheters with one to six unilateral side holes), and bilateral side hole model (six catheters with one to six bilateral side holes). Catheters were inserted into a drainage output-measuring device with a constant-pressure reservoir of water. The volume of water evacuated by each of the catheters at 10-second intervals was measured. A total of five trials were performed for each catheter. Data were analysed using one-way analysis of variance. RESULTS: The open-ended catheter had a mean drainage volume comparable to the unilateral model catheters with three, four, and five side holes. Unilateral model catheters had significant drainage volume increases up to three side holes; unilateral model catheters with more than three side holes had no significant improvement in drainage volume. All bilateral model catheters had significantly higher mean drainage volumes than their unilateral counterparts. There was no significant difference between the mean drainage volume with one, two, or three pairs of bilateral side holes. Further, there was no drainage improvement by adding additional bilateral side holes. CONCLUSION: The present in vitro study suggests that beyond a critical side hole number threshold, adding more distal side holes does not improve catheter drainage efficiency. These results may be used to enhance catheter design towards improving their drainage efficiency.

IL-1ß reduces tonic contraction of mesenteric lymphatic muscle cells, with the involvement of cycloxygenase-2 and prostaglandin E2.

BACKGROUND AND PURPOSE: The lymphatic system maintains tissue homeostasis by unidirectional lymph flow, maintained by tonic and phasic contractions within subunits, 'lymphangions'. Here we have studied the effects of the inflammatory cytokine IL-1ß on tonic contraction of rat mesenteric lymphatic muscle cells (RMLMC). EXPERIMENTAL APPROACH: We measured IL-1ß in colon-conditioned media (CM) from acute (AC-CM, dextran sodium sulfate) and chronic (CC-CM, T-cell transfer) colitis-induced mice and corresponding controls (Con-AC/CC-CM). We examined tonic contractility of RMLMC in response to CM, the cytokines h-IL-1ß or h-TNF-α (5, 10, 20 ng·mL(-1) ), with or without COX inhibitors [TFAP (10(-5) M), diclofenac (0.2 × 10(-5) M)], PGE2 (10(-5) M)], IL-1-receptor antagonist, Anakinra (5 µg·mL(-1) ), or a selective prostanoid EP4 receptor antagonist, GW627368X (10(-6) and 10(-7) M). KEY RESULTS: Tonic contractility of RMLMC was reduced by AC- and CC-CM compared with corresponding control culture media, Con-AC/CC-CM. IL-1ß or TNF-α was not found in Con-AC/CC-CM, but detected in AC- and CC-CM. h-IL-1ß concentration-dependently decreased RMLMC contractility, whereas h-TNF-α showed no effect. Anakinra blocked h-IL-1ß-induced RMLMC relaxation, and with AC-CM, restored contractility to RMLMC. IL-1ß increased COX-2 protein and PGE2 production in RMLMC.. PGE2 induced relaxations in RMLMC, comparable to h-IL-1ß. Conversely, COX-2 and EP4 receptor inhibition reversed relaxation induced by IL-1ß. CONCLUSIONS AND IMPLICATIONS: The IL-1ß-induced decrease in RMLMC tonic contraction was COX-2 dependent, and mediated by PGE2 . In experimental colitis, IL-1ß and tonic lymphatic contractility were causally related, as this cytokine was critical for the relaxation induced by AC-CM and pharmacological blockade of IL-1ß restored tonic contraction.

Acute oral Bryostatin-1 administration improves learning deficits in the APP/PS1 transgenic mouse model of Alzheimer's disease.

BACKGROUND: Previous studies showed that Bryostatin-1, a potent PKC modulator and alphasecretase activator, can improve cognition in models of Alzheimer's disease (AD) with chronic (>10 weeks), intraperitoneal (i.p.) administration of the drug. We compared learning and spatial memory in the APPswe, PSEN1dE985Dbo (APP/PS1) mouse model of AD and studied the ability of acute intraperitoneal and oral Bryostatin-1 to reverse cognitive deficits in this model. Compared to wild-type (WT) mice, APP/PS1 mice showed significant delays in learning the location of a submerged platform in the Morris water maze. Bryostatin-1 was administered over a 2-week course prior to and during water maze testing. RESULTS: Acute i.p. Bryostatin-1 administration did not improve latency to escape but oral Bryostatin-1 significantly improved memory (measured by a reduction in latency to escape). This benefit of oral Bryostatin-1 administration was most apparent during the first 3 days of testing. These findings show that: 1) Bryostatin-1 is orally active in models of learning and memory, 2) this effect can be produced in less than 2 weeks and 3) this effect is not seen with i.p. administration. We conclude that oral Bryostatin-1 represents a novel, potent and long-acting memory enhancer with future clinical applications in the treatment of human AD.