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Background Motor recovery after stroke in humans and in rodent models is time sensitive. Recovery in patients is a result of biological spontaneous recovery via endogenous repair mechanisms and is likely improved by enhancing the synaptic plasticity required for endogenous repair. Cerebrolysin is a polypeptide preparation known to enhance neuroplasticity and may improve recovery in patients. In mice, we tested the hypothesis that Cerebrolysin can act poststroke to enhance both spontaneous and training-associated motor recovery. Methods Mice were trained to perform a skilled prehension task. We then induced a photothrombotic stroke in the caudal forelimb area, after which we retrained animals on the prehension task in the presence or absence of Cerebrolysin after a 2-day or 8-day delay. Mice received daily intraperitoneal Cerebrolysin or saline injections starting poststroke day 1 or poststroke day 7. Results Prior studies showed that poststroke recovery of prehension can occur if animals receive rehabilitative training during an early sensitive period but is incomplete if rehabilitative training is delayed. In contrast, we show complete recovery of prehension, despite a delay in rehabilitative training, when mice receive daily Cerebrolysin administration starting on poststroke day 1 or on poststroke day 8. When Cerebrolysin is given on poststroke day 1, recovery occurred even in the absence of training. Stroke volumes were similar across groups. Conclusions Poststroke Cerebrolysin administration leads to recovery of motor function independent of rehabilitative training without a protective effect on stroke volume. This is one of the first demonstrations of training-independent motor recovery in rodent stroke models.

CC-91516 (also called CC0776314), a selective and potent inhibitor of ERK1/2 and NLK, was discovered via a phenotypic screen of a kinase-focused library for compounds that synergize with mTOR kinase inhibitor CC-223 to induce apoptosis in combination with CC-223. Broad kinase selectivity profiling identified ERK1/2 and NLK as targets of CC-91516. Crystal structure of CC-91516 in complex with ERK2 reveals that its 2, 4, 6-trichlorophenyl moiety binds to a unique back pocket of the adenosine-5′-triphosphate (ATP) binding site of ERK2, which is not accessible to other ERK inhibitors such as BVD-523 and GDC-0994. This unique binding mode of CC-91516 leads to a slow off-rate for its ERK binding with long residence time disrupting both the active and inactive ERK forms. Consequentially, CC-91516 causes sustained inhibition of the MAPK pathway in BRAF mutant colorectal cancer cells. In addition, CC-91516 also regulates Wnt/β-catenin and YAP pathways in multiple cancer cell lines. CC-91516 shows potent yet selective anti-proliferative activity against a large panel of cancer cell lines. Activating mutations in BRAF or CTNNB1 gene associate with sensitivity to CC-91516-mediated anti-proliferative activity while mutations in RB and PI3K/PTEN pathway associate with resistance. CC-91516 inhibits ex vivo colony formation of PDX models with BRAF and CTNNB1 mutations. In addition, CC-91516 potently induces apoptosis, inhibits survival, and overcomes resistance to MEK inhibitor trametinib of BRAF or CTNNB1 mutant cancer cells in long-term culture assay in vitro. CC-91516 has good oral bioavailability and shows excellent anti-tumor activity in vivo against both BRAF and CTNNB1 mutant xenograft models. DMPK and toxicology studies showed robust oral exposure across preclinical species. In summary, CC-91516 has demonstrated preclinical anti-tumor activities and DMPK and safety profiles in support of its clinical development. Citation Format: Shuichan Xu, Tam Tran, Dan Zhu, Tao Shi, David Mikolon, Jim Leisten, Philip Chamberlain, Laurie LeBrun, Sogole Bahmanyar, Ning Jiang, Jingjing Zhao, Mehnaz Malek, Ellen Filvaroff, Heather Raymon, Robert Hubbard, John Boylan. Discovery of CC-91516, a potent and selective ERK/NLK inhibitor, with anti-tumor activity in preclinical cancer models harboring BRAF or CTNNB1 mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1180.

We describe a method to introduce naive mice to a novel prehension (reach-to-grasp) task. Mice are housed singly in cages with a frontal slot that permits the mouse to reach out of its cage and retrieve food pellets. Minimal food restriction is employed to encourage the mice to perform the food retrieval from the slot. As the mice begin to associate coming to the slot for food, the pellets are manually pulled away to stimulate extension and pronation of their paw to grasp and retrieve the pellet through the frontal slot. When the mice begin to reach for the pellets as they arrive at the slot, the behavioral assay can be performed by measuring the rate at which they successfully grasp and retrieve the desired pellet. They are then introduced to an auto-trainer that automates both the process of providing food pellets for the mouse to grasp, and the recording of successful and failed reaching and grasping attempts. This allows for the collection of reaching data for multiple mice with minimal effort, to be used in experimental analysis as appropriate.

Background and Purpose: Most functional upper extremity motor recovery occurs in the first 4 weeks after ischemic stroke in humans and in the first week in rodent models. The majority of functional recovery in humans is spontaneous (i.e. occurs as a result of endogenous repair processes rather than rehabilitative interventions). In mouse models of stroke, recovery is impaired when post-stroke rehabilitation is delayed and there is very little spontaneous recovery. Cerebrolysin is a polypeptide preparation shown to enhance neuronal plasticity and to promote motor recovery in patients after stroke. In mice, we tested the hypothesis that Cerebrolysin can act early after stroke to enhance spontaneous motor recovery. Methods: Adult C57Bl/6 mice were trained to perform a skilled prehension task to an asymptotic level of performance, after which they underwent photocoagulation-induced stroke in the caudal forelimb area (rodent primary motor cortex). The mice were then randomized to receive Cerebrolysin or saline injections beginning 24-hours post-stroke. Both groups were then retrained at the same prehension task by a blinded investigator. Stroke volumes were compared using immunohistochemistry. Results: We have previously shown that training-associated recovery of prehension is complete if training is initiated after a 1-day delay but incomplete if training is initiated after a 7-day delay, even with additional training days. However, daily Cerebrolysin administration after stroke was associated with complete recovery of prehension by day 8, even in the absence of training. Stroke volumes were similar across all groups. Conclusions: We conclude that Cerebrolysin administration during an early time window can lead to spontaneous recovery of motor function without a protective effect on stroke volume. This is one of the first demonstrations of spontaneous motor recovery in a rodent stroke model. Our mouse model, with all of the attendant genetic benefits, should allow us to determine at the cellular and molecular level how endogenous plasticity and medications like Cerebrolysin interact to mediate recovery.

Background and objective. Prior studies have suggested that after stroke there is a time-limited period of increased responsiveness to training as a result of heightened plasticity—a sensitive period thought to be induced by ischemia itself. Using a mouse model, we have previously shown that most training-associated recovery after a caudal forelimb area (CFA) stroke occurs in the first week and is attributable to reorganization in a medial premotor area (AGm). The existence of a stroke-induced sensitive period leads to the counterintuitive prediction that a second stroke should reopen this window and promote full recovery from the first stroke. To test this prediction, we induced a second stroke in the AGm of mice with incomplete recovery after a first stroke in CFA. Methods. Mice were trained to perform a skilled prehension (reach-to-grasp) task to an asymptotic level of performance, after which they underwent photocoagulation-induced stroke in CFA. After a 7-day poststroke delay, the mice were then retrained to asymptote. We then induced a second stroke in the AGm, and after only a 1-day delay, retrained the mice. Results. Recovery of prehension was incomplete when training was started after a 7-day poststroke delay and continued for 19 days. However, a second focal stroke in the AGm led to a dramatic response to 9 days of training, with full recovery to normal levels of performance. Conclusions. New ischemia can reopen a sensitive period of heightened responsiveness to training and mediate full recovery from a previous stroke.

Background and Purpose— Data from both humans and animal models suggest that most recovery from motor impairment after stroke occurs in a sensitive period that lasts only weeks and is mediated, in part, by an increased responsiveness to training. Here, we used a mouse model of focal cortical stroke to test 2 hypotheses. First, we investigated whether responsiveness to training decreases over time after stroke. Second, we tested whether fluoxetine, which can influence synaptic plasticity and stroke recovery, can prolong the period over which large training-related gains can be elicited after stroke. Methods— Mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent stroke induction in the caudal forelimb area. The mice were then retrained after a 1- or 7-day delay with and without fluoxetine. Results— Recovery of prehension after a caudal forelimb area stroke was complete if training was initiated 1 day after stroke but incomplete if it was delayed by 7 days. In contrast, if fluoxetine was administered at 24 hours after stroke, then complete recovery of prehension was observed even with the 7-day training delay. Fluoxetine seemed to mediate its beneficial effect by reducing inhibitory interneuron expression in intact premotor cortex rather than through effects on infarct volume or cell death. Conclusions— There is a gradient of diminishing responsiveness to motor training over the first week after stroke. Fluoxetine can overcome this gradient and maintain maximal levels of responsiveness to training even 7 days after stroke.

Background: and purpose - Data in humans and in non-human animal models suggest that most recovery from motor impairment occurs in the first 4 weeks after stroke and is mediated in part by increased responsiveness to training in this short time period. We tested the hypothesis that there is a gradient of diminishing responsiveness to training in the first week after stroke in the mouse. We then tested whether fluoxetine can extend the time window over which large training-related gains can be expected. Methods: Adult C57Bl/6 mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent photocoagulation-induced stroke or sham stroke in the caudal forelimb area (CFA can be considered rodent primary motor cortex). The mice were then retrained after a 1- or 7-day delay in the presence or absence of fluoxetine injected IP daily beginning after a 1- or 7-day delay. Results: Training-associated recovery of prehension was complete if training was initiated after a 1-day delay but incomplete if training was initiated after a 7-day delay, even with additional training days. Daily fluoxetine administration after stroke was associated with complete recovery of prehension even if training was delayed 7 days but only if fluoxetine was administered beginning 1 day but not 7 days after stroke. Conclusions: We conclude that there is a sensitive period 7 days after stroke during which motor training is more likely to promote recovery and that this period can be extended by fluoxetine only if administration begins during the first week after stroke. Our mouse model, with all of the attendant genetic benefits, may allow us to determine at the cellular and molecular level how behavioral training and endogenous plasticity interact to mediate recovery.

Abstract The soaring cost of drilling in deep-water environments leads to a strong demand for high-quality interpretable images and associated models, both products of seismic imaging, in many basins around the world. Anisotropic models more closely represent the real earth's properties. Using them in migration increases our ability to create accurate images. Overall, this allows for more reliable inversion, interpretation, and drilling decisions. In addition, anisotropic imaging allows us to realize fully the potential of new data types (e.g., wide-azimuth and long-offsets towed-streamer data) and to incorporate systematically our understanding of the geology, the available rock physics and geomechanics information, and borehole data into the model building process. We discuss an anisotropic model building workflow that is easily adaptable to any geologic environment, data type, objectives, or available non-seismic information. We report successful imaging strategies made possible by this workflow and demonstrate the improved results with examples from North America and West Africa. Introduction Advances in seismic imaging are, arguably, the most important element in the rising success of deep-water exploration and development because they reduce interpretation and drilling risk to acceptable levels. Historically, anisotropic imaging was applied only on smaller projects in mature fields with abundant well data. In recent years, the demand for high-quality pre-salt and subsalt images made anisotropic depth imaging with vertical transverse isotropic (VTI) and tilted transverse isotropic (TTI) models the dominant industry practice, even for large-scale exploration projects in areas of limited well control, i.e., the majority of the deep-water basins around the world. In parallel, new data types (wide- and full-azimuth towed-streamer) were introduced and more advanced demultiple, migration, and inversion algorithms became available. Figure 1 illustrates the cumulative effect of all these improvements, comparing isotropic imaging with 2006 narrow-azimuth (NAZ) data with a VTI imaging result in the same area using 2011 wide-azimuth (WAZ) data. The much-improved and detailed velocity model follows the geology closely (Figure 1 b) and naturally translates into an image with better focusing, better event continuity, less reflector distortion, and more easily interpretable events at depths more than 30,000 ft below the autochthonous salt. In complex geologic situations, the improved images resulting from well-designed anisotropic imaging carry potential beyond that of typical structural and stratigraphic interpretation. In cases with thoughtful conditioning of the migrated amplitude data, careful calibration of well and seismic data, validation of amplitude fidelity, and preparation of appropriate background trend models, quantitative interpretation methods can be applied in situations previously thought to be off limits for quantitative work (Wagner et al., 2012). In addition, high-quality velocity models obtained during anisotropic imaging allow quantification of structural uncertainty for volumetric analysis (Osypov et al., 2011). Through such approaches, be it subsalt or pre-salt, reservoir development in deepwater environments can greatly benefit from recent advances in imaging.

s. Woodward, M., D. Nichols, O. Zdraveva, P. Whitfield, and T. Johns, 2008, A decade of tomography: Geophysics, 73, no. 5, VE5–VE11, doi:10.1190/1.2969907. Zdraveva, O., A. Bakulin, and Y. Liu, 2010, Building geologically plausible anisotropic models using well data and horizon-guided interpolation: First Break, 28, no. 9, 77–80. Zdraveva, O., and M. Cogan, 2011, Building anisotropic models for large scale TTI imaging in areas with limited well control: Kwanza basin case study: 73rd EAGE Conference & Exhibition, Extended

Many commercial materials sold in bulk form occur as particulates or pellets at some intermediate stage in their production. Detection of defects and foreign particles at this stage is a useful quality control function. This paper describes a concept and implementation for measuring contaminant count and removing undesirable material from a product stream. The system in its present form is restricted to materials that exhibit low optical loss. Many polymers and other particulates fall into this category or are sufficiently close that the system functions effectively. An optical scanner and material transport system are integrated with a computer system to perform the detection and sorting functions. Throughputs of 60 lbs/hour have been demonstrated and higher rates are possible.© (1992) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Described in detail in the main body of the paper is a circular slide rule designed to use for many calculations where the seismic velocity varies linearly with distance from a datum plane (usually horizontal), i.e., where [Formula: see text]. Here [Formula: see text] is the velocity at datum and a is the rate of change of velocity with respect to depth z. Table I lists, in the first column, data that must be given and, in the second column, what may be found from it by using the present slide rule. Except for that of line 10, all calculations are limited only by the accuracy of reading the scales, which is sufficient for most practical purposes. The calculation of line 10 is approximate only, but needs correcting over only about 5 percent of its usually used range; this correction is very simply made.