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Eye-hand coordination (EHC) is crucial to our daily activities, and its underlying mechanisms are being intensely studied. The analysis of simultaneous eye and hand movements can provide valuable insights into EHC, particularly for individuals struggling with dexterous control, such as might be caused by stroke or traumatic brain injuries. Despite advancements in motion-capture and eye tracking technologies, there is currently no automated method for visualizing concurrent eye- and hand-movement data. To address this need, we have developed a MATLAB-based dashboard designed for near instantaneous analysis and visualization of eye and hand-tracking data. This paper introduces the design of the dashboard and presents experimental results obtained from its application, leveraging simulated data inspired by our recent work in stroke. This testing suggests that our solution has the potential to significantly aid in understanding and investigating EHC by providing side-by-side and time-locked comparison of eye/hand movements along with their timing and spatio-temporal errors, offering novel opportunities for research and clinical applications. • Continuous eye movement data is collected throughout the experiment • Continuous hand movement data is collected throughout the experiment • Combine datasets and display time-locked eye-hand data in a single dashboard

Objective: The present study evaluated the acceptance among parents of newborns to the creatine kinase (CK) test in the neonatal screening of Duchenne Muscular Dystrophy-DMD and raised possible barriers and elements that facilitate the acceptance of the test. Methods: The assessment of acceptance of the CK test for DMD screening was carried out through interviews, guided by a semi-structured script, with parents of newborns in the state of Mato Grosso, Brazil. Results: Six hundred and four parents participated in the research, only five being excluded for not meeting the eligibility criteria. The acceptance of screening among respondents was high (94.5%), surpassing that described in the retrieved literature. Long journeys to the collection site and the absence of information about the disease and the CK test can negatively influence parents regarding the performance of the test. The reduction in diagnostic delay seems to be a positive factor in the acceptance of screening. Conclusions: Non-mandatory neonatal screening for DMD using the CK test demonstrated high acceptance by the interviewed population; however, research has identified factors that can both motivate and discourage screening.

Oceanic islands and seamounts play an important role on the origin and maintenance of biodiversity, however, these environments are still poorly understood. Here we report 15 new records of reef fish species for the Davis Seamount, Trindade Island and Martin Vaz Archipelago, in the Vitoria-Trindade Chain (VTC). Such isolated sites are among the last frontier for shallow reef exploration in the South Atlantic, and more scientific effort is needed to better understand their biogeography and to help in conservation efforts.

Neste trabalho, objetivou-se estudar a resposta espectral de plantas de feijoeiro à infecção por Sclerotinia sclerotiorum, fungo causador do mofo-branco. Foram conduzidos dois ensaios, no delineamento em blocos ao acaso, com cinco tratamentos e quatro repetições, no primeiro ensaio, e seis tratamentos e quatro repetições, no segundo. Medidas de reflectância espectral do dossel do feijoeiro, entre os comprimentos de ondas de 400 a 850 nm, foram tomadas aos 60, 71, 91 e 102 dias após a emergência (DAE), no primeiro ensaio, e aos 13, 27, 34, 56, 71 e 91 DAE, no segundo. Os dados espectrais foram transformados em índices de vegetação: da diferença normalizada (NDVI), da diferença de verde normalizado (GNDVI) e ajustado para o solo (SAVI). A severidade do mofo-branco foi avaliada, visualmente, aos 102 DAE, no primeiro ensaio, e aos 92 DAE, no segundo. Houve correlação significativa apenas no segundo ensaio, entre a severidade da doença e o NDVI, aos 71 DAE. A resposta espectral do feijoeiro pode ser utilizada para a detecção da ocorrência do mofo-branco e, consequentemente, como ferramenta no manejo integrado.

The bean cultivar BRSMG União as a new option of a bean cultivar with jalo grains for the state of Minas Gerais. The cultivar BRSMG União had an average grain yield of 9.8% above the mean of the controls (Jalo EEP 558 and BRS Radiante) and was resistant to powdery-mildew.

The cultivar BRSMG Madrepérola, recommended for cultivation in Minas Gerais, has the feature of maintaining a light grain color for a longer period than other Carioca grain cultivars. The yield potential is high and the resistance level good to the major anthracnose races in the region.

Neste trabalho buscou-se averiguar as percepções dos egressos da UFMT quanto à formação profissional e adequabilidade das condições oferecidas pela instituição em sua formação. Com uma participação de 529 ex-alunos, os dados foram processados nos softwares SPSS e IRAMUTEQ. Os resultados apontam bons níveis de satisfação com a estrutura e formação oferecida pela Instituição. Criticas e Sugestões são excelentes ferramentas para o crescimento e amadurecimento dos gestores.

In this study we analyze the population structure and diet of the coney Cephalopholis fulva at Trindade Island, Brazil, through direct observation with SCUBA diving in 11 reef sites around the Island, up to 50 m deep. Diet was based on 77 individuals collected with speargun. Mean population density and biomass were estimated at 29 individuals/100 m² and 13 kg/100 m², respectively. This species is regularly distributed along the costal environments of the Trindade Island, with no significant differences in densities and biomass detected among the different collection habitats (reef crest, reef slope, and reef plateau). However, significantly higher densities were observed micro-habitats with greater structural complexity, which may offer more shelter and food to C. fulva. Four food item groups were identified from the gut contents of C. fulva: Annelida, Crustacea, Teleostei, and Testudinata. It is the first record of predation of the green turtle Chelonia mydas hatchlings by the coney. Trindade Island seems to present the densest concentration of C. fulva in all Brazilian and Caribbean ecosystems inhabited by this species. Scarcity of competitors, predators, and fishing pressure may explain the high densities observed in the Island.Foram analisadas a estrutura populacional e a dieta do catuá Cephalopholis fulva na Ilha da Trindade, Brasil. Os dados foram obtidos através de censos visuais com mergulho autônomo em 11 locais no entorno da ilha, em profundidades de até 50 m. A dieta e a proporção sexual foram baseadas na análise de 77 indivíduos coletados com arpão. A densidade populacional e biomassa foram estimados em 29 indivíduos/m² e 13 kg/100 m², respectivamente. A espécie apresentou distribuição uniforme nos ambientes costeiros da ilha, não tendo sido registradas diferenças significativa em sua densidade e biomassa entre os diferentes habitats estudados (crista, talude e platô recifal). Entretanto, foi observado preferência por micro-habitats de alta complexidade estrutural. Foram registrados quatro grupos de itens alimentares no conteúdo estomacal de C. fulva: Annelida, Crustacea, Teleostei e Testudinata. É feito aqui o primeiro registro de predação de juvenis da tartaruga-verde (Chelonia mydas) por C. fulva. Trindade parece apresentar os maiores valores de densidade para o catuá, quando comparada a outras localidades do Brasil e Caribe. A escassez de competidores, predadores e a pressão pesqueira são possíveis fatores que podem explicar as altas densidades observadas para C. fulva na Ilha da Trindade.

Visual records, radio interviews and onboard observations of the fishing activities during a 58 days scientific expedition to Trindade Island and the Martin Vaz Archipelago were obtained from February to April 2007. The regular activities of four different fisheries were observed: pelagic longline, bottom line, trolling and handline. These fisheries caused mortality of at least seven species with some level threat, according to the International Union for Conservation of Nature list. The establishment of specific restriction norms for hook-and-line activities around the oceanic islands was seen as an alternative for the conservation of the ichthyofauna of the region. Satellite monitoring to track the fishery vessels could be established through the national program as another legal mean to diminish fishing the impact.Reportamos atividades de pesca comerciais no complexo insular mais afastado da costa brasileira: Ilha da Trindade e Arquipélago Martin Vaz. As atividades foram estudadas através de embarques e entrevistas com os mestres e pescadores das embarcações durante uma expedição cientifica realizada entre fevereiro e abril de 2007. Quatro modalidades de atividades de pesca são realizadas na região, capturando ao menos sete espécies que possuem algum risco de extinção. O estabelecimento de normas específicas de restrição para atividades que pescam sobre os recifes das ilhas é uma alternativa para a conservação das espécies ameaçadas. O monitoramento das embarcações pode ocorrer via satélite através do programa nacional de rastreamento de embarcações pesqueiras (PREPS).

With the purpose to evaluate the intensity of angular leaf spot (ALS) and anthracnose (ANT) on pods, nine genotypes of common bean were planted in three cropping systems: monocrop (MC), monocrop grown on trellises (MCT), and intercrop with maize (ICM). In MC, beans were planted 0.5 m apart. Trelisses were set up with 1.8 m high bamboos and beans were sown 0.65 m apart. In ICM, beans were planted simultaneously with maize and in its rows. This cereal was sown 1.0 m apart with four plants per meter. Each cropping system was an independent trial installed close to each other. Climbing genotypes of beans most susceptible to ALS had less diseased pods in ICM than in both MC and MCT, but the less susceptible genotypes, regardless of their growth type, as well as the susceptible bush and semiclimbing genotypes, were similarly attacked by ALS in the three systems. ANT on pods of the susceptible bean cv. Pérola was less intense in MCT than in MC, and less intense in ICM than in MCT. ANT seed transmission was 11 %, 9.1 %, and 4.4 % when seeds come from MC, MCT, and ICM, respectively.Com o objetivo de avaliar a intensidade da mancha-angular (MA) e da antracnose (ANT) em vagens, nove genótipos de feijão foram plantados em três sistemas de plantio: monocultivo (MC), monocultivo com tutoragem artificial (MCT) e consórcio com milho (CCM). No MC, o feijão foi semeado no espaçamento entre fileiras de 0,50 m. Para o MCT, utilizaram-se varas de bambu formando "Vs" invertidos com 1,8 m de altura, nos quais foi mantido o espaçamento entre fileiras de 0,65 m na base. No CCM, o feijão foi plantado simultaneamente ao milho e em suas fileiras. Esse cereal foi semeado no espaçamento de 1,0 m, com quatro plantas por metro. Cada sistema de cultivo foi um ensaio independente, todos instalados na mesma área. Os genótipos trepadores mais suscetíveis à MA apresentaram menos vagens doentes no CCM que no MC e MCT, mas os genótipos menos atacados pela MA, independentemente do tipo de crescimento, como também os outros genótipos suscetíveis de porte anão e semitrepador, foram infectados de forma semelhante nos três sistemas de plantio. A ANT nas vagens do cv. Pérola foi menos intensa no MCT que no MC, e menos intensa no CCM que no MCT. A transmissão da ANT pela semente foi de 11 %, 9,1 % e 4,4 % quando as sementes foram colhidas no MC, MCT e CCM, respectivamente.

Acremonium strictum é patogênico ao milho e a outras culturas, podendo causar podridão de sementes, podridão de colmos e a morte de plântulas. Trata-se de um fungo que pode interferir no vigor, estande e produtividade final das plantas. Além disso, pode ser disseminado e transmitido à progênie via sementes, ainda que não sejam conhecidas as proporções reais em que isso ocorre. Neste trabalho, avaliou-se o efeito de A. strictum nas qualidades fisiológica e sanitária de sementes e plântulas, no crescimento vegetativo e na sanidade (taxas de infecção e de transmissão) de plantas de milho em seu estádio inicial de desenvolvimento. As taxas de infecção e de transmissão do fungo foram avaliadas usando-se a técnica da restrição hídrica, previamente desenvolvida para infectar as sementes. O meio MA (extrato de malte-ágar), suplementado com manitol para obter o potencial de água de -1,4 MPa, foi o substrato utilizado na inoculação das sementes. Observou-se que a germinação das sementes de milho foi reduzida por A. strictum em períodos de contato com a colônia fúngica acima de 72 horas. O vigor e a viabilidade potenciais das sementes de milho não foram afetados pela presença de A. strictum. Após 28 dias da semeadura, a incidência de A. strictum reduziu o crescimento vegetativo de plantas de milho. O fungo A. strictum, oriundo de sementes inoculadas, foi transmitido às plantas jovens de milho.Acremonium strictum is pathogenic to seeds, stalk and seedlings of maize. It is a fungus that can interfere in the vigor, stand and final productivity of plants. In addition, it can be disseminated and transmitted through seeds to the progeny, although the real proportions of that are not well known. This study reports the effects of A. strictum on maize seeds and seedlings quality (germination, vigor, healthness), some vegetative growth parameters and also sanity (infection and transmission rates) of young maize plants. The transmission rate of the fungus was evaluated using the water restriction technique. The fungus formulation was cultivated on malt extract agar medium amended with mannitol to a water potential of -1,4 MPa. The maize seeds germination was reduced by seeds exposition to A. strictum for periods longer than 72 hours. The potentials vigor and viability were not affected by A. strictum. Theincidence of this fungus reduced the vegetative growth of maize plants measured 28 days after sowing. The fungus originating from inoculated seeds was transmitted to young maize plants.

In this study we analyze the population structure and diet of the coney Cephalopholis fulva at Trindade Island, Brazil, through direct observation with SCUBA diving in 11 reef sites around the Island, up to 50 m deep. Diet was based on 77 individuals collected with speargun. Mean population density and biomass were estimated at 29 individuals/100 m² and 13 kg/100 m², respectively. This species is regularly distributed along the costal environments of the Trindade Island, with no significant differences in densities and biomass detected among the different collection habitats (reef crest, reef slope, and reef plateau). However, significantly higher densities were observed micro-habitats with greater structural complexity, which may offer more shelter and food to C. fulva. Four food item groups were identified from the gut contents of C. fulva: Annelida, Crustacea, Teleostei, and Testudinata. It is the first record of predation of the green turtle Chelonia mydas hatchlings by the coney. Trindade Island seems to present the densest concentration of C. fulva in all Brazilian and Caribbean ecosystems inhabited by this species. Scarcity of competitors, predators, and fishing pressure may explain the high densities observed in the Island.

Goal: Distance information is highly requested in assistive smartphone Apps by people who are blind or low vision (PBLV). However, current techniques have not been evaluated systematically for accuracy and usability. Methods: We tested five smartphone-based distance-estimation approaches in the image center and periphery at 1-3 meters, including machine learning (CoreML), infrared grid distortion (IR&#95;self), light detection and ranging (LiDAR&#95;back), and augmented reality room-tracking on the front (ARKit&#95;self) and back-facing cameras (ARKit&#95;back). Results: For accuracy in the image center, all approaches had <±2.5 cm average error, except CoreML which had ±5.2-6.2 cm average error at 2-3 meters. In the periphery, all approaches were more inaccurate, with CoreML and IR&#95;self having the highest average errors at ±41 cm and ±32 cm respectively. For usability, CoreML fared favorably with the lowest central processing unit usage, second lowest battery usage, highest field-of-view, and no specialized sensor requirements. Conclusions: We provide key information that helps design reliable smartphone-based visual assistive technologies to enhance the functionality of PBLV., (© 2024 The Authors.)

Background: Blind/low vision (BLV) severely limits information about our three-dimensional world, leading to poor spatial cognition and impaired navigation. BLV engenders mobility losses, debility, illness, and premature mortality. These mobility losses have been associated with unemployment and severe compromises in quality of life. VI not only eviscerates mobility and safety but also, creates barriers to inclusive higher education. Although true in almost every high-income country, these startling facts are even more severe in low- and middle-income countries, such as Thailand. We aim to use VIS 4 ION (Visually Impaired Smart Service System for Spatial Intelligence and Onboard Navigation), an advanced wearable technology, to enable real-time access to microservices, providing a potential solution to close this gap and deliver consistent and reliable access to critical spatial information needed for mobility and orientation during navigation., Methods: We are leveraging 3D reconstruction and semantic segmentation techniques to create a digital twin of the campus that houses Mahidol University's disability college. We will do cross-over randomization, and two groups of randomized VI students will deploy this augmented platform in two phases: a passive phase, during which the wearable will only record location, and an active phase, in which end users receive orientation cueing during location recording. A group will perform the active phase first, then the passive, and the other group will experiment reciprocally. We will assess for acceptability, appropriateness, and feasibility, focusing on experiences with VIS 4 ION. In addition, we will test another cohort of students for navigational, health, and well-being improvements, comparing weeks 1 to 4. We will also conduct a process evaluation according to the Saunders Framework. Finally, we will extend our computer vision and digital twinning technique to a 12-block spatial grid in Bangkok, providing aid in a more complex environment., Discussion: Although electronic navigation aids seem like an attractive solution, there are several barriers to their use; chief among them is their dependence on either environmental (sensor-based) infrastructure or WiFi/cell "connectivity" infrastructure or both. These barriers limit their widespread adoption, particularly in low-and-middle-income countries. Here we propose a navigation solution that operates independently of both environmental and Wi-Fi/cell infrastructure. We predict the proposed platform supports spatial cognition in BLV populations, augmenting personal freedom and agency, and promoting health and well-being., Trial Registration: ClinicalTrials.gov under the identifier: NCT03174314, Registered 2017.06.02., (© 2023. The Author(s).)

Vision-based localization approaches now underpin newly emerging navigation pipelines for myriad use cases, from robotics to assistive technologies. Compared to sensor-based solutions, vision-based localization does not require pre-installed sensor infrastructure, which is costly, time-consuming, and/or often infeasible at scale. Herein, we propose a novel vision-based localization pipeline for a specific use case: navigation support for end users with blindness and low vision. Given a query image taken by an end user on a mobile application, the pipeline leverages a visual place recognition (VPR) algorithm to find similar images in a reference image database of the target space. The geolocations of these similar images are utilized in a downstream task that employs a weighted-average method to estimate the end user's location. Another downstream task utilizes the perspective-n-point (PnP) algorithm to estimate the end user's direction by exploiting the 2D-3D point correspondences between the query image and the 3D environment, as extracted from matched images in the database. Additionally, this system implements Dijkstra's algorithm to calculate a shortest path based on a navigable map that includes the trip origin and destination. The topometric map used for localization and navigation is built using a customized graphical user interface that projects a 3D reconstructed sparse map, built from a sequence of images, to the corresponding a priori 2D floor plan. Sequential images used for map construction can be collected in a pre-mapping step or scavenged through public databases/citizen science. The end-to-end system can be installed on any internet-accessible device with a camera that hosts a custom mobile application. For evaluation purposes, mapping and localization were tested in a complex hospital environment. The evaluation results demonstrate that our system can achieve localization with an average error of less than 1 m without knowledge of the camera's intrinsic parameters, such as focal length.

Sialidosis type 1 is a rare lysosomal storage disorder caused by mutations of the neuraminidase gene. Specific features suggesting this condition include myoclonus, ataxia and macular cherry-red spots. However, phenotypic variability exists. Here, we present detailed clinical and video description of three patients with this rare condition. We also provide an in-depth characterization of eye movement abnormalities, as an additional tool to investigate pathophysiological mechanisms and to facilitate diagnosis. In our patients, despite phenotypic differences, eye movement deficits largely localized to the cerebellum., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2021 The Author(s).)

(1) Background: The King-Devick (KD) rapid number naming test is sensitive for concussion diagnosis, with increased test time from baseline as the outcome measure. Eye tracking during KD performance in concussed individuals shows an association between inter-saccadic interval (ISI) (the time between saccades) prolongation and prolonged testing time. This pilot study retrospectively assesses the relation between ISI prolongation during KD testing and cognitive performance in persistently-symptomatic individuals post-concussion. (2) Results: Fourteen participants (median age 34 years; 6 women) with prior neuropsychological assessment and KD testing with eye tracking were included. KD test times (72.6 ± 20.7 s) and median ISI (379.1 ± 199.1 msec) were prolonged compared to published normative values. Greater ISI prolongation was associated with lower scores for processing speed (WAIS-IV Coding, r = 0.72, p = 0.0017), attention/working memory (Trails Making A, r = -0.65, p = 0.006) (Digit Span Forward, r = 0.57, p = -0.017) (Digit Span Backward, r = -0.55, p = 0.021) (Digit Span Total, r = -0.74, p = 0.001), and executive function (Stroop Color Word Interference, r = -0.8, p = 0.0003). (3) Conclusions: This pilot study provides preliminary evidence suggesting that cognitive dysfunction may be associated with prolonged ISI and KD test times in concussion.

Background: Eye-hand coordination (EHC) is a sophisticated act that requires interconnected processes governing synchronization of ocular and manual motor systems. Precise, timely and skillful movements such as reaching for and grasping small objects depend on the acquisition of high-quality visual information about the environment and simultaneous eye and hand control. Multiple areas in the brainstem and cerebellum, as well as some frontal and parietal structures, have critical roles in the control of eye movements and their coordination with the head. Although both cortex and cerebellum contribute critical elements to normal eye-hand function, differences in these contributions suggest that there may be separable deficits following injury., Method: As a preliminary assessment for this perspective, we compared eye and hand-movement control in a patient with cortical stroke relative to a patient with cerebellar stroke., Result: We found the onset of eye and hand movements to be temporally decoupled, with significant decoupling variance in the patient with cerebellar stroke. In contrast, the patient with cortical stroke displayed increased hand spatial errors and less significant temporal decoupling variance. Increased decoupling variance in the patient with cerebellar stroke was primarily due to unstable timing of rapid eye movements, saccades., Conclusion: These findings highlight a perspective in which facets of eye-hand dyscoordination are dependent on lesion location and may or may not cooperate to varying degrees. Broadly speaking, the results corroborate the general notion that the cerebellum is instrumental to the process of temporal prediction for eye and hand movements, while the cortex is instrumental to the process of spatial prediction, both of which are critical aspects of functional movement control.

Iterative liver injury results in progressive fibrosis disrupting hepatic architecture, regeneration potential, and liver function. Hepatic stellate cells (HSCs) are a major source of pathological matrix during fibrosis and are thought to be a functionally homogeneous population. Here, we use single-cell RNA sequencing to deconvolve the hepatic mesenchyme in healthy and fibrotic mouse liver, revealing spatial zonation of HSCs across the hepatic lobule. Furthermore, we show that HSCs partition into topographically diametric lobule regions, designated portal vein-associated HSCs (PaHSCs) and central vein-associated HSCs (CaHSCs). Importantly we uncover functional zonation, identifying CaHSCs as the dominant pathogenic collagen-producing cells in a mouse model of centrilobular fibrosis. Finally, we identify LPAR1 as a therapeutic target on collagen-producing CaHSCs, demonstrating that blockade of LPAR1 inhibits liver fibrosis in a rodent NASH model. Taken together, our work illustrates the power of single-cell transcriptomics to resolve the key collagen-producing cells driving liver fibrosis with high precision., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The motor system executes actions in a highly stereotyped manner despite the high number of degrees of freedom available. Studies of motor adaptation leverage this fact by disrupting, or perturbing, visual feedback to measure how the motor system compensates. To elicit detectable effects, perturbations are often large compared to trial-to-trial reach endpoint variability. However, awareness of large perturbations can elicit qualitatively different compensation processes than unnoticeable ones can. The current experiment measures the perturbation detection threshold, and investigates how humans combine proprioception and vision to decide whether displayed reach endpoint errors are self-generated only, or are due to experimenter-imposed perturbation. We scaled or rotated the position of the visual feedback of center-out reaches to targets and asked subjects to indicate whether visual feedback was perturbed. Subjects detected perturbations when they were at least 1.5 times the standard deviation of trial-to-trial endpoint variability. In contrast to previous studies, subjects suboptimally combined vision and proprioception. Instead of using proprioceptive input, they responded based on the final (possibly perturbed) visual feedback. These results inform methodology in motor system experimentation, and more broadly highlight the ability to attribute errors to one's own motor output and combine visual and proprioceptive feedback to make decisions.

Intratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity to uncover requirements for a T cell-driven response compatible with checkpoint inhibitors (CPIs). In contrast to high-dose tumor ablative regimens that result in systemic S100 distribution, low-dose immunogenic regimens induce local activation of tumor-specific CD8 + effector T cells that are responsible for durable anti-tumor immunity and can be enhanced with CPIs. Both hematopoietic cell STING expression and signaling through IFNAR are required for tumor-specific T cell activation, and in the context of optimized T cell responses, TNFα is dispensable for tumor control. In a poorly immunogenic model, S100 combined with CPIs generates a survival benefit and durable protection. These results provide fundamental mechanistic insights into STING-induced anti-tumor immunity., (Copyright © 2018 Aduro Biotech, Inc. Published by Elsevier Inc. All rights reserved.)

Agents that remodel the tumor microenvironment (TME), prime functional tumor-specific T cells, and block inhibitory signaling pathways are essential components of effective immunotherapy. We are evaluating live-attenuated, double-deleted Listeria monocytogenes expressing tumor antigens (LADD-Ag) in the clinic. Here we show in numerous mouse models that while treatment with nonrecombinant LADD induced some changes in the TME, no antitumor efficacy was observed, even when combined with immune checkpoint blockade. In contrast, LADD-Ag promoted tumor rejection by priming tumor-specific KLRG1 + PD1 lo CD62L - CD8 + T cells. These IFNγ-producing effector CD8 + T cells infiltrated the tumor and converted the tumor from an immunosuppressive to an inflamed microenvironment that was characterized by a decrease in regulatory T cells (Treg) levels, a proinflammatory cytokine milieu, and the shift of M2 macrophages to an inducible nitric oxide synthase (iNOS) + CD206 - M1 phenotype. Remarkably, these LADD-Ag-induced tumor-specific T cells persisted for more than 2 months after primary tumor challenge and rapidly controlled secondary tumor challenge. Our results indicate that the striking antitumor efficacy observed in mice with LADD-based immunotherapy stems from TME remodeling which is a direct consequence of eliciting potent, systemic tumor-specific CD8 + T cells., Competing Interests: Conflict of interest statement: W.D., V.L., T.E.H., E.E.L., W.G.H., R.F., G.B., G.E.K., A.L.D., P.L., M.L.L., and T.W.D. are current or former paid employees of Aduro Biotech, and hold stock in the company. D.A.P. was supported by National Institutes of Health Grants 1P01 AI063302 and 1R01 AI027655 and a Grant from Aduro Biotech (IVRI). D.A.P. has a consulting relationship with and a financial interest in Aduro Biotech, and both he and the company stand to benefit from the commercialization of the results of this research., (Copyright © 2018 the Author(s). Published by PNAS.)

Background: The King-Devick (K-D) test of rapid number naming is a reliable visual performance measure that is a sensitive sideline indicator of concussion when time scores worsen (lengthen) from preseason baseline. Within cohorts of youth athletes <18 years old, baseline K-D times become faster with increasing age. We determined the relation of rapid number-naming time scores on the K-D test to electronic measurements of saccade performance during preseason baseline assessments in a collegiate ice hockey team cohort. Within this group of young adult athletes, we also sought to examine the potential role for player age in determining baseline scores., Methods: Athletes from a collegiate ice hockey team received preseason baseline testing as part of an ongoing study of rapid rink-side performance measures for concussion. These included the K-D test (spiral-bound cards and tablet computer versions). Participants also performed a laboratory-based version of the K-D test with simultaneous infrared-based video-oculographic recordings using an EyeLink 1000+. This allowed measurement of the temporal and spatial characteristics of eye movements, including saccadic velocity, duration, and intersaccadic interval (ISI)., Results: Among 13 male athletes, aged 18-23 years (mean 20.5 ± 1.6 years), prolongation of the ISI (a combined measure of saccade latency and fixation duration) was the measure most associated with slower baseline time scores for the EyeLink-paired K-D (mean 38.2 ± 6.2 seconds, r = 0.88 [95% CI 0.63-0.96], P = 0.0001), the K-D spiral-bound cards (36.6 ± 5.9 seconds, r = 0.60 [95% CI 0.08-0.87], P = 0.03), and K-D computerized tablet version (39.1 ± 5.4 seconds, r = 0.79 [95% CI 0.42-0.93], P = 0.001). In this cohort, older age was a predictor of longer (worse) K-D baseline time performance (age vs EyeLink-paired K-D: r = 0.70 [95% CI 0.24-0.90], P = 0.008; age vs K-D spiral-bound cards: r = 0.57 [95% CI 0.03-0.85], P = 0.04; age vs K-D tablet version: r = 0.59 [95% CI 0.06-0.86], P = 0.03) as well as prolonged ISI (r = 0.62 [95% CI 0.11-0.87], P = 0.02). Slower baseline K-D times were not associated with greater numbers of reported prior concussions., Conclusions: Rapid number-naming performance using the K-D at preseason baseline in this small cohort of collegiate ice hockey players is best correlated with ISI among eye movement-recording measures. Baseline K-D scores notably worsened with increasing age, but not with numbers of prior concussions in this small cohort. While these findings require further investigation by larger studies of contact and noncontact sports athletes, they suggest that duration of contact sports exposure may influence preseason test performance.

Objective: To determine the feasibility and efficacy of using a structured Nintendo Wii protocol to improve range of motion, strength, and quality of life in patients with shoulder impingement syndrome., Methods: A total of 14 patients with shoulder pain were randomized to perform a structured Wii protocol (n=8) or conventional therapy (n=6). Pain-free shoulder range of motion, strength, shoulder pain and disability, and quality of life were assessed pre- and post-treatment., Results: All 8 patients completed the Wii protocol, and 3 completed conventional therapy. The Wii protocol conferred significant improvements in shoulder range of motion, pain and disability, and quality of life but not strength, whereas conventional therapy conferred a significant improvement in strength., Conclusions: As compared to conventional treatment, the structured Wii protocol implemented in this pilot study was a viable adjunct to therapy for shoulder impingement syndrome. Gaming may have a supplemental benefit by increasing motivation, pleasure, and/or adherence. Further investigation in larger cohorts is warranted., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

It is widely accepted that cerebral pathology can impair ocular motor and manual motor control. This is true in indolent and chronic processes, such as neurodegeneration and in acute processes such as stroke or those secondary to neurotrauma. More recently, it has been suggested that disruptions in these control systems are useful markers for prognostication and longitudinal monitoring. The utility of examining the relationship or the coupling between these systems has yet to be determined. We measured eye and hand-movement control in chronic, middle cerebral artery stroke, relative to healthy controls, in saccade-to-reach paradigms to assess eye-hand coordination. Primary saccades were initiated significantly earlier by stroke participants relative to control participants. However, despite these extremely early initial saccades to the target, reaches were nevertheless initiated at approximately the same time as those of control participants. Control participants minimized the time period between primary saccade onset and reach initiation, demonstrating temporal coupling between eye and hand. In about 90% of all trials, control participants produced no secondary, or corrective, saccades, instead maintaining fixation in the terminal position of the primary saccade until the end of the reach. In contrast, participants with stroke increased the time period between primary saccade onset and reach initiation. During this temporal decoupling, multiple saccades were produced in about 50% of the trials with stroke participants making between one and five additional saccades. Reaches made by participants with stroke were both longer in duration and less accurate. In addition to these increases in spatial reach errors, there were significant increases in saccade endpoint errors. Overall, the magnitude of the endpoint errors for reaches and saccades were correlated across participants. These findings suggest that in individuals with otherwise intact visual function, the spatial and temporal relationships between the eye and hand are disrupted poststroke, and may need to be specifically targeted during neurorehabilitation. Eye-hand coupling may be a useful biomarker in individuals with cerebral pathology in the setting of neurovascular, neurotraumatic, and neurodegenerative pathology.

Acute and chronic disease processes that lead to cerebral injury can often be clinically challenging diagnostically, prognostically, and therapeutically. Neurodegenerative processes are one such elusive diagnostic group, given their often diffuse and indolent nature, creating difficulties in pinpointing specific structural abnormalities that relate to functional limitations. A number of studies in recent years have focused on eye-hand coordination (EHC) in the setting of acquired brain injury (ABI), highlighting the important set of interconnected functions of the eye and hand and their relevance in neurological conditions. These experiments, which have concentrated on focal lesion-based models, have significantly improved our understanding of neurophysiology and underscored the sensitivity of biomarkers in acute and chronic neurological disease processes, especially when such biomarkers are combined synergistically. To better understand EHC and its connection with ABI, there is a need to clarify its definition and to delineate its neuroanatomical and computational underpinnings. Successful EHC relies on the complex feedback- and prediction-mediated relationship between the visual, ocular motor, and manual motor systems and takes advantage of finely orchestrated synergies between these systems in both the spatial and temporal domains. Interactions of this type are representative of functional sensorimotor control, and their disruption constitutes one of the most frequent deficits secondary to brain injury. The present review describes the visually mediated planning and control of eye movements, hand movements, and their coordination, with a particular focus on deficits that occur following neurovascular, neurotraumatic, and neurodegenerative conditions. Following this review, we also discuss potential future research directions, highlighting objective EHC as a sensitive biomarker complement within acute and chronic neurological disease processes.

Saccades rapidly direct the line of sight to targets of interest to make use of the high acuity foveal region of the retina. These fast eye movements are instrumental for scanning visual scenes, foveating targets, and, ultimately, serve to guide manual motor control, including eye-hand coordination. Cerebral injury has long been known to impair ocular motor control. Recently, it has been suggested that alterations in control may be useful as a marker for recovery. We measured eye movement control in a saccade task in subjects with chronic middle cerebral artery stroke with both cortical and substantial basal ganglia involvement and in healthy controls. Saccade latency distributions were bimodal, with an early peak at 60 ms (anticipatory saccades) and a later peak at 250 ms (regular saccades). Although the latencies corresponding to these peaks were the same in the two groups, there were clear differences in the size of the peaks. Classifying saccade latencies relative to the saccade "go signal" into anticipatory (latencies up to 80 ms), "early" (latencies between 80 and 160 ms), and "regular" types (latencies longer than 160 ms), stroke subjects displayed a disproportionate number of anticipatory saccades, whereas control subjects produced the majority of their saccades in the regular range. We suggest that this increase in the number of anticipatory saccade events may result from a disinhibition phenomenon that manifests as an impairment in the endogenous control of ocular motor events (saccades) and interleaved fixations. These preliminary findings may help shed light on the ocular motor deficits of neurodegenerative conditions, results that may be subclinical to an examiner, but clinically significant secondary to their functional implications.

Objective: The King-Devick (KD) test, which is based on rapid number naming speed, is a performance measure that adds vision and eye movement assessments to sideline concussion testing. We performed a laboratory-based study to characterize ocular motor behavior during the KD test in a patient cohort with chronic concussion to identify features associated with prolonged KD reading times., Methods: Twenty-five patients with a concussion history (mean age: 31) were compared to control participants with no concussion history ( n = 42, mean age: 32). Participants performed a computerized KD test under infrared-based video-oculography., Results: Average intersaccadic intervals for task-specific saccades were significantly longer among concussed patients compared to controls (324.4 ± 85.6 msec vs. 286.1 ± 49.7 msec, P = 0.027). Digitized KD reading times were prolonged in concussed participants versus controls (53.43 ± 14.04 sec vs. 43.80 ± 8.55 sec, P = 0.004) and were highly correlated with intersaccadic intervals. Concussion was also associated with a greater number of saccades during number reading and larger average deviations of saccade endpoint distances from the centers of the to-be-read numbers (1.22 ± 0.29° vs. 0.98 ± 0.27°, P = 0.002). There were no differences in saccade peak velocity, duration, or amplitude., Interpretation: Prolonged intersaccadic intervals, greater numbers of saccades, and larger deviations of saccade endpoints underlie prolonged KD reading times in chronic concussion. The KD test relies upon a diffuse neurocognitive network that mediates the fine control of efferent visual function. One sequela of chronic concussion may be disruption of this system, which may produce deficits in spatial target selection and planning of eye movements.

A coordinate system is composed of an encoding, defining the dimensions of the space, and an origin. We examine the coordinate encoding used to update motor plans during sensory-motor adaptation to center-out reaches. Adaptation is induced using a novel paradigm in which feedback of reach endpoints is perturbed following a sinewave pattern over trials; the perturbed dimensions of the feedback were the axes of a Cartesian coordinate system in one session and a polar coordinate system in another session. For center-out reaches to randomly chosen target locations, reach errors observed at one target will require different corrections at other targets within Cartesian- and polar-coded systems. The sinewave adaptation technique allowed us to simultaneously adapt both dimensions of each coordinate system (x-y, or reach gain and angle), and identify the contributions of each perturbed dimension by adapting each at a distinct temporal frequency. The efficiency of this technique further allowed us to employ perturbations that were a fraction the size normally used, which avoids confounding automatic adaptive processes with deliberate adjustments made in response to obvious experimental manipulations. Subjects independently corrected errors in each coordinate in both sessions, suggesting that the nervous system encodes both a Cartesian- and polar-coordinate-based internal representation for motor adaptation. The gains and phase lags of the adaptive responses are not readily explained by current theories of sensory-motor adaptation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The Toll-like receptor 4 agonist glucopyranosyl lipid adjuvant formulated in a stable emulsion (GLA-SE) promotes strong TH1 and balanced IgG1/IgG2 responses to protein vaccine antigens. This enhanced immunity is sufficient to provide protection against many diseases including tuberculosis and leishmaniasis. To better characterize the adjuvant action it is important to understand how the different cytokines and transcription factors contribute to the initiation of immunity. In the present study using T-bet-/- and IL-12-/- mice and a blocking anti-IFNαR1 monoclonal antibody, we define mechanisms of adjuvant activity of GLA-SE. In accordance with previous studies of TLR4 agonist based adjuvants, we found that TH1 induction via GLA-SE was completely dependent upon T-bet, a key transcription factor for IFNγ production and TH1 differentiation. Consistent with this, deficiency of IL-12, a cytokine canonical to TH1 induction, ablated TH1 induction via GLA-SE. Finally we demonstrate that the innate immune response to GLA-SE, including rapid IFNγ production by memory CD8+ T cells and NK cells, was contingent on type I interferon, a cytokine group whose association with TH1 induction is contextual, and that they contributed to the adjuvant activity of GLA-SE.

Healthy individuals appear to use both vector-coded reach plans that encode movements in terms of their desired direction and extent, and target-coded reach plans that encode the desired endpoint position of the effector. We examined whether these vector and target reach-planning codes are differentially affected after stroke. Participants with stroke and healthy controls made blocks of reaches that were grouped by target location (providing target-specific practice) and by movement vector (providing vector-specific practice). Reach accuracy was impaired in the more affected arm after stroke, but not distinguishable for target- versus vector-grouped reaches. Reach velocity and acceleration were not only impaired in both the less and more affected arms poststroke, but also not distinguishable for target- versus vector-grouped reaches. As previously reported in controls, target-grouped reaches yielded isotropic (circular) error distributions and vector-grouped reaches yielded error distributions elongated in the direction of the reach. In stroke, the pattern of variability was similar. However, the more affected arm showed less elongated error ellipses for vector-grouped reaches compared to the less affected arm, particularly in individuals with right-hemispheric stroke. The results suggest greater impairment to the vector-coded movement-planning system after stroke, and have implications for the development of personalized approaches to poststroke rehabilitation: Motor learning may be enhanced by practice that uses the preserved code or, conversely, by retraining the more impaired code to restore function., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

With over eight million cases of tuberculosis each year there is a pressing need for the development of new vaccines against Mycobacterium tuberculosis. Subunit vaccines consisting of recombinant proteins are an attractive vaccine approach due to their inherent safety compared to attenuated live vaccines and the uniformity of manufacture. Addition of properly formulated TLR agonist-containing adjuvants to recombinant protein vaccines enhances the antigen-specific CD4(+) T cell response characterized by IFN-γ and TNF, both of which are critical for the control of TB. We have developed a clinical stage vaccine candidate consisting of a recombinant fusion protein ID93 adjuvanted with the TLR4 agonist GLA-SE. Here we examine whether ID93+GLA-SE can be improved by the addition of a second TLR agonist. Addition of CpG containing DNA to ID93+GLA-SE enhanced the magnitude of the multi-functional TH1 response against ID93 characterized by co-production of IFN-γ, TNF, and IL-2. Addition of CpG also improved the protective efficacy of ID93+GLA-SE. Finally we demonstrate that this adjuvant synergy between GLA and CpG is independent of TRIF signaling, whereas TRIF is necessary for the adjuvant activity of GLA-SE in the absence of CpG.

Coordinate systems for movement planning are comprised of an anchor point (e.g., retinocentric coordinates) and a representation (encoding) of the desired movement. One of two representations is often assumed: a final-position code describing desired limb endpoint position and a vector code describing movement direction and extent. The existence of movement-planning systems using both representations is controversial. In our experiments, participants completed reaches grouped by target location (providing practice for a final-position code) and the same reaches grouped by movement vector (providing vector-code practice). Target-grouped reaches resulted in the isotropic (circular) distribution of errors predicted for position-coded reaches. The identical reaches grouped by vector resulted in error ellipses aligned with the reach direction, as predicted for vector-coded reaches. Manipulating only recent movement history to provide better learning for one or the other movement code, we provide definitive evidence that both movement representations are used in the identical task.

In the study of visual-motor control, perhaps the most familiar findings involve adaptation to externally imposed movement errors. Theories of visual-motor adaptation based on optimal information processing suppose that the nervous system identifies the sources of errors to effect the most efficient adaptive response. We report two experiments using a novel perturbation based on stimulating a visually induced reflex in the reaching arm. Unlike adaptation to an external force, our method induces a perturbing reflex within the motor system itself, i.e., perturbing forces are self-generated. This novel method allows a test of the theory that error source information is used to generate an optimal adaptive response. If the self-generated source of the visually induced reflex perturbation is identified, the optimal response will be via reflex gain control. If the source is not identified, a compensatory force should be generated to counteract the reflex. Gain control is the optimal response to reflex perturbation, both because energy cost and movement errors are minimized. Energy is conserved because neither reflex-induced nor compensatory forces are generated. Precision is maximized because endpoint variance is proportional to force production. We find evidence against source-identified adaptation in both experiments, suggesting that sensory-motor information processing is not always optimal.

We analyze the problem of obstacle avoidance from a Bayesian decision-theoretic perspective using an experimental task in which reaches around a virtual obstacle were made toward targets on an upright monitor. Subjects received monetary rewards for touching the target and incurred losses for accidentally touching the intervening obstacle. The locations of target-obstacle pairs within the workspace were varied from trial to trial. We compared human performance to that of a Bayesian ideal movement planner (who chooses motor strategies maximizing expected gain) using the Dominance Test employed in Hudson et al. (2007). The ideal movement planner suffers from the same sources of noise as the human, but selects movement plans that maximize expected gain in the presence of that noise. We find good agreement between the predictions of the model and actual performance in most but not all experimental conditions.

When movement outcome differs consistently from the intended movement, errors are used to correct subsequent movements (e.g., adaptation to displacing prisms or force fields) by updating an internal model of motor and/or sensory systems. Here, we examine changes to an internal model of the motor system under changes in the variance structure of movement errors lacking an overall bias. We introduced a horizontal visuomotor perturbation to change the statistical distribution of movement errors anisotropically, while monetary gains/losses were awarded based on movement outcomes. We derive predictions for simulated movement planners, each differing in its internal model of the motor system. We find that humans optimally respond to the overall change in error magnitude, but ignore the anisotropy of the error distribution. Through comparison with simulated movement planners, we found that aimpoints corresponded quantitatively to an ideal movement planner that updates a strictly isotropic (circular) internal model of the error distribution. Aimpoints were planned in a manner that ignored the direction-dependence of error magnitudes, despite the continuous availability of unambiguous information regarding the anisotropic distribution of actual motor errors.

Macrophages are required for tissue homeostasis through their role in regulation of the immune response and the resolution of injury. Here we show, using the kidney as a model, that the Wnt pathway ligand Wnt7b is produced by macrophages to stimulate repair and regeneration. When macrophages are inducibly ablated from the injured kidney, the canonical Wnt pathway response in kidney epithelial cells is reduced. Furthermore, when Wnt7b is somatically deleted in macrophages, repair of injury is greatly diminished. Finally, injection of the Wnt pathway regulator Dkk2 enhances the repair process and suggests a therapeutic option. Because Wnt7b is known to stimulate epithelial responses during kidney development, these findings suggest that macrophages are able to rapidly invade an injured tissue and reestablish a developmental program that is beneficial for repair and regeneration.

Understanding the origin of myofibroblasts in kidney is of great interest because these cells are responsible for scar formation in fibrotic kidney disease. Recent studies suggest epithelial cells are an important source of myofibroblasts through a process described as the epithelial-to-mesenchymal transition; however, confirmatory studies in vivo are lacking. To quantitatively assess the contribution of renal epithelial cells to myofibroblasts, we used Cre/Lox techniques to genetically label and fate map renal epithelia in models of kidney fibrosis. Genetically labeled primary proximal epithelial cells cultured in vitro from these mice readily induce markers of myofibroblasts after transforming growth factor beta(1) treatment. However, using either red fluorescent protein or beta-galactosidase as fate markers, we found no evidence that epithelial cells migrate outside of the tubular basement membrane and differentiate into interstitial myofibroblasts in vivo. Thus, although renal epithelial cells can acquire mesenchymal markers in vitro, they do not directly contribute to interstitial myofibroblast cells in vivo. Lineage analysis shows that during nephrogenesis, FoxD1-positive((+)) mesenchymal cells give rise to adult CD73(+), platelet derived growth factor receptor beta(+), smooth muscle actin-negative interstitial pericytes, and these FoxD1-derivative interstitial cells expand and differentiate into smooth muscle actin(+) myofibroblasts during fibrosis, accounting for a large majority of myofibroblasts. These data indicate that therapeutic strategies directly targeting pericyte differentiation in vivo may productively impact fibrotic kidney disease.

Although horizontal binocular retinal disparity between images in the two eyes resulting from their different views of the world has long been the centerpiece for understanding the unique characteristics of stereovision, it does not suffice to explain many binocular phenomena. Binocular depth contrast (BDC), the induction of an appearance of visual pitch in a centrally located line by pitched-from-vertical flanking lines, has particularly been the subject of a good deal of attention in this regard. In the present article, we show that BDC does not cross the median plane but is restricted to the side of the visual field containing a unilateral inducer. These results cannot be explained by the use of retinal disparity alone or in combination with any additional factors or processes previously suggested to account for stereovision. We present a two-channel three-stage neuromathematical model that accounts quantitatively for present and previous BDC results and also accounts for a large number of the most prominent features of binocular pitch perception: Stage 1 of the differencing channel obtains the difference between the retinal orientations of the images in the two eyes separately for the inducer and the test line; stage 1 of the summing channel obtains the corresponding sums. Signals from inducer and test stimuli are combined linearly in each channel in stage 2, and in stage 3 the outputs from the two channels are combined along with a bias signal from the body-referenced mechanism to yield ', the model's prediction for the perception of pitch.

Motor control requires the generation of a precise temporal sequence of control signals sent to the skeletal musculature. We describe an experiment that, for good performance, requires human subjects to plan movements taking into account uncertainty in their movement duration and the increase in that uncertainty with increasing movement duration. We do this by rewarding movements performed within a specified time window, and penalizing slower movements in some conditions and faster movements in others. Our results indicate that subjects compensated for their natural duration-dependent temporal uncertainty as well as an overall increase in temporal uncertainty that was imposed experimentally. Their compensation for temporal uncertainty, both the natural duration-dependent and imposed overall components, was nearly optimal in the sense of maximizing expected gain in the task. The motor system is able to model its temporal uncertainty and compensate for that uncertainty so as to optimize the consequences of movement.

We examined how subjects plan speeded reaching movements when the precise target of the movement is not known at movement onset. Before each reach, subjects were given only a probability distribution on possible target positions. Only after completing part of the movement did the actual target appear. In separate experiments we varied the location of the mode and the scale of the prior distribution for possible targets. In both cases we found that subjects made use of prior probability information when planning reaches. We also devised two tests (Composite Benefit and Row Dominance tests) to determine whether subjects' performance met necessary conditions for optimality (defined as maximizing expected gain). We could not reject the hypothesis of optimality in the experiment where we varied the mode of the prior, but departures from optimality were found in response to changes in the scale of prior distributions.

Statistical decision theory suggests that choosing an ideal action requires taking several factors into account: (1) prior knowledge of the probability of various world states, (2) sensory information concerning the world state, (3) the probability of outcomes given a choice of action, and (4) the loss or gain associated with those outcomes. In previous work, we found that, in many circumstances, humans act like ideal decision makers in planning a reaching movement. They select a movement aim point that maximizes expected gain, thus taking into account outcome uncertainty (motor noise) and the consequences of their actions. Here, we ask whether humans can optimally combine prior knowledge and uncertain sensory information in planning a reach. Subjects rapidly pointed at unseen targets, indicated with dots drawn from a distribution centered on the invisible target location. Target location had a prior distribution, the form of which was known to the subject. We varied the number of dots and hence target spatial uncertainty. An analysis of the sources of uncertainty impacting performance in this task indicated that the optimal strategy was to aim between the mean of the prior (the screen center) and the mean stimulus location (centroid of the dot cloud). With increased target location uncertainty, the aim point should have moved closer to the prior. Subjects used near-optimal strategies, combining stimulus uncertainty and prior information appropriately. Observer behavior was well modeled as having three additional sources of inefficiency originating in the motor system, calculation of centroid location, and calculation of aim points.