Auditory and visual systems organization in Brodmann Area 8 for gaze-shift control: where we do not see, we can hear

Hearing is especially important for most primate species as they live in habitats of dense vegetation that limits vision. Stebbins (1980) summed up the evolution of the auditory system by assuming that earliest mammals exploited nocturnal niches since they were relatively free of many of the large, diurnal, predacious reptiles. Therefore, hearing and smell were more useful at night than vision. Our vision is limited not only in the dark but also outside the visual field. In fact, if we observe the behavior of a predator like a feline, oriented toward its prey, and at the same time a sound occurs behind, we might note three principal different behaviors: the predator could maintain its gaze and ears on the prey neglecting the sound source; the predator could maintain its gaze on the prey rotating ears and then shifting its auditory attention toward the sound source; finally the predator could break its attention and orient gaze and ears toward the sound source. A similar behavior is seen in human beings during social interaction with two or more interlocutors. In humans, orienting movements are carried out by the eyes, head, and/or body operating alone or in various combinations depending on the behavioral situation. However, in non-human primates, such as macaque monkeys, head orienting movements and, more generally, gaze-shift are accompanied by ear orienting movements, which allow the shifting of auditory attention toward a sound of interest (Bon and Lucchetti, 1994, 2006; Lucchetti et al., 2008; Lanzilotto et al., 2013; Yin, 2013). Considering all these assumptions, the auditory system could have an important role to detect information even from regions of the space that the visual system cannot explore without orienting movements. In other words, where we cannot see, we can hear. Through this opinion article, we argue that Brodmann Area 8 receives information from both auditory and visual systems and organizes a transformation of these sensory signals into gaze-shift motor commands. Our hypothesis is that this sensory-motor transformation is spatially organized, from both anatomical and functional points of view. Anatomical and functional properties of the Brodmann Area 8 (consisting in Area 8A plus Area 8B) support a medio-lateral organization for both auditory and visual systems. In particular, the lateral portion, corresponding to Area 8A or Frontal Eye Field (FEF), could play a role in receiving visual and auditory information from a central part of the visual field and then in organizing gaze-shift motor commands toward it. Otherwise, the medial portion, corresponding to Area 8B or Premotor Ear-Eye Field (PEEF), could play a role in receiving principally auditory information from a peripheral region of the space and then in organizing gaze-shift motor commands toward it

Evidence for a functional subdivision of Premotor Ear-Eye Field (Aera 8B)

The Supplementary EyeField (SEF) and the Frontal Eye Field (FEF) have been described as participating in gaze shift control. Recent evidence suggests, however, that other areas of the dorso medial prefrontal cortex also influence gaze shift. Herein, we haveinvestigated electrically evoked ear-and eye movements from the PremotorEar-Eye Field, or PEEF (area8B) of macaque monkeys. We stimulated PEEF during spontaneous condition (outside the task performance) and during the execution of a visual fixation task(VFT). In the first case, we functionally identified two regions within the PEEF: a core and a belt. In the core region, stimulation elicited forward ear movements; regarding the evoked eye movements, in some penetrations, stimulation elicited contraversive fixed-vectors with a mean amplitude of 5.14◦; while in other penetrations, we observed prevalently contralateral goal-directed eye movements having end-points that fell within15◦ inrespect to the primary eye position. On the contrary, in the belt region,stimulation elicited backward ear movements; regarding the eye movements, in some penetrations stimulation elicited prevalently contralateral goal-directed eye movements having end-points that fell within 15◦ in respect to the primary eye position, while in the lateral edge of the investigated region, stimulation elicited contralateral goal-directedey emovements having end-points that fell beyond 15◦in respect to the primary eye position. Stimulation during VFT either did not elicit eye movements or evoked saccades of only a few degrees. Finally, even though no head rotation movements were observed during the stimulation period, we viewed a relationship between the duration of stimulation and the neck forces exerted by the monkey’shead. We propose an updated vision of the PEEF composed of two functional regions, core and belt, which may beinvolved in integrating auditory and visual information important to the programming of gaze orienting movements

Neuronal Encoding of Self and Others' Head Rotation in the Macaque Dorsal Prefrontal Cortex.

Following gaze is a crucial skill, in primates, for understanding where and at what others are looking, and often requires head rotation. The neural basis underlying head rotation are deemed to overlap with the parieto-frontal attention/gaze-shift network. Here, we show that a set of neurons in monkey's Brodmann area 9/46dr (BA 9/46dr), which is involved in orienting processes and joint attention, becomes active during self head rotation and that the activity of these neurons cannot be accounted for by saccade-related activity (head-rotation neurons). Another set of BA 9/46dr neurons encodes head rotation performed by an observed agent facing the monkey (visually triggered neurons). Among these latter neurons, almost half exhibit the intriguing property of encoding both execution and observation of head rotation (mirror-like neurons). Finally, by means of neuronal tracing techniques, we showed that BA 9/46dr takes part into two distinct networks: a dorso/mesial network, playing a role in spatial head/gaze orientation, and a ventrolateral network, likely involved in processing social stimuli and mirroring others' head. The overall results of this study provide a new, comprehensive picture of the role of BA 9/46dr in encoding self and others' head rotation, likely playing a role in head-following behaviors

A kinematic study of skilled reaching movement in rat

Abstract BACKGROUND: In the rat, the single-pellet reaching task includes orienting, reaching, grasping and retracting movements. It has previously been described by notation techniques, high-speed video and cineradiographic recordings. Recently, high-definition cameras have been used to track paw and digit movements with DeepLabCut, a machine-learning algorithm for markerless estimation of paw position. NEW METHOD: Our new approach consists of positioning three high-speed infrared digital cameras to track the full motion of markers on the rat's body. This provided a previously unavailable 3D recording of skilled reaching kinematics in the rat moving freely in the reaching box, which were analysed by Qualisys Track Manager software and MATLAB. RESULTS: This method enabled description of kinematic parameters unobtainable without motion tracking and provided insight into the spatiotemporal metrics of movements used to perform skilled reaching. It revealed that orientation features three steps and reaching has two bimodal start-point distributions, one along the horizontal axis and one along the vertical axis. At the end of reaching, the wrist/paw occupies the same position as the nose at the end of orienting. In grasping, averaging trajectories confirmed the marker lowering and target approaching. COMPARISON WITH EXISTING METHODS: Our method required significantly reduced time to label data and obviates the need for off-line manual marking of videos. It provides an efficient means of capturing volumes containing the entire range of marker movements. CONCLUSIONS: This study validated a new and efficient approach for quantifying rat movement kinematics, useful for comparing preclinical and clinical conditions

Transferable Fishing Concessions (TFC): A pilot study on the applicability in the Mediterranean Sea

Fisheries management systems based on Transferable Fishing Concessions (TFC) and similar rights-based systems have been developed during the last decades in some European countries. However, at present there is not a clear view on the possible effects caused by the application of this management systems in the Mediterranean Sea. The current study, involving nine Geographical Sub-Areas (GSAs) of the Mediterranean Sea, focuses on the appropriateness, transferability and modes of applicability of a TFC system in the Mediterranean area. Three different scenarios of quota allocation have been analyzed by taking into account biological, ecological, environmental, economic and social aspects: quota in terms of resource quantity, quota as a portion of the total fishing time, quota as a portion of the total fishing capacity. Results show that the transferability of a TFC-based system to the Mediterranean context appears to be low due to the characteristics of the Mediterranean fisheries (multispecificity of resources, fishing grounds shared among different countries, multigear, importance of small-scale fisheries) and to the general lack of sound and reliable individual historical data. The study also highlights rights-based systems such as Territorial Use Rights in Fisheries (TURF) might only be applied for the exploitation of sedentary resources, such as clams. A management system based on TFC could be theoretically reasonable for anchovy fishing, where a few species are caught, even if all countries and stakeholders should be involved in the decision making process

Clinical utility of plasma KRAS, NRAS and BRAF mutational analysis with real time PCR in metastatic colorectal cancer patients -The importance of tissue/plasma discordant cases

Background: Tumor tissue (T) mutational analysis represents the standard for metastatic colorectal cancer (mCRC); however, circulating tumor DNA (ctDNA) detected by liquid biopsy in plasma (PL) can better represent tumor heterogeneity. Methods: mCRC patients undergoing standard first-line chemotherapy with known T-KRAS/NRAS/BRAF status were enrolled in the present prospective study. PL mutations were assessed within 2 weeks before chemotherapy start with real time PCR and correlated with T status and Progression free survival (PFS). Clinical and biochemical variables including also total number of tumor lesions (TNL) and the sum of maximum diameter (SMD) of all lesions were assessed as potential predictors of T/PL discordance. RESULTS: Among 45 enrolled patients, all BRAF mutations were concordant between T and PL and there were 20% of patients RAS discordant: 9% wild type in T and mutated in PL and 11% mutated in T and wild type in PL. T mutations were significantly associated to median PFS (mPFS of 4.5, 8.3 and 22.9 months for T-BRAF mutated, T-RAS mutated, and T-wild type patients, respectively, p for trend 0.00014). PL mutations further refined prognosis: RAS wild type in T and mutated in PL had significantly shorter PFS than concordant RAS wild type in T and PL: mPFS 9.6 vs. 23.3 months, respectively, p = 0.02. Patients RAS mutated in T and wild type in PL had longer PFS than concordant RAS mutated in T and PL: 24.4 vs. 7.8 months, respectively, p = 0.008. At a multivariate cox regression analysis for PFS, PL mutations were independent prognostic factor superior to T analysis (HR 0.13, p = 0.0008). At multivariate logistic regression analysis TNL and SMD were significant predictors of discordant cases. Conclusions: PL mutational analysis allows a better prognostication than T analysis alone and could help in mCRC treatment management

Análisis de los cambios y dificultades surgidas después del trasplante renal: una investigación cualitativa

;;OBJECTIVE:;; to identify the main gains and stressors perceived by the patient, one year subsequent to kidney transplantation.;;;;METHOD:;; a qualitative study, in which the data were obtained and analyzed through the Discourse of the Collective Subject and frequency counting, with the participation of 50 patients who had received kidney transplantation.;;;;RESULTS:;; the sample presented a mean age of 44±12.8 years old, and a predominance of males (62%). The principal positive changes provided by the transplant were: return to activities; freedom/independence; well-being and health; strengthening of the I; and closening of interpersonal relationships. The most-cited stressors were: fear; medication; excess of care/control; specific characteristics of the treatment; and failure to return to the social roles.;;;;CONCLUSION:;; kidney transplantation caused various positive changes in the patient's routine, with the return to activities of daily living being the most important gain, in the participants' opinion. In relation to the stressors, fear related to loss of the graft, and questions relating to the immunosuppressive medication were the main challenges to be faced following transplantation.;;;;OBJETIVO:;; identificar os principais ganhos e estressores percebidos pelo paciente, após um ano de transplante renal.;;;;MÉTODO:;; trata-se de um estudo qualitativo, em que os dados foram obtidos e analisados através do Discurso do Sujeito Coletivo e contagem de frequência, com a participação de 50 pacientes transplantados renais.;;;;RESULTADOS:;; a amostra apresentou média de idade de 44±12,8 anos e predominância do sexo masculino (62%). As principais mudanças positivas proporcionadas pelo transplante foram: retorno às atividades; liberdade/independência; bem-estar e saúde; fortalecimento do eu; e estreitamento das relações interpessoais. Os estressores mais citados foram: medo; medicação; excesso de cuidado/controle; particularidades do tratamento; e não retorno aos papéis sociais.;;;;CONCLUSÃO:;; o transplante renal proporcionou várias mudanças positivas à rotina do paciente, sendo o retorno às atividades de vida diária o ganho mais importante, na opinião dos participantes. Quanto aos estressores, o medo relacionado à perda do enxerto e questões relativas ao medicamento imunossupressor foram os principais desafios a serem enfrentados após o transplante.;;;;OBJETIVO:;; identificar las principales ganancias y estresores percibidos por el paciente, después de un año de trasplante renal.;;;;MÉTODO:;; se trata de un estudio cualitativo, en que los datos fueron obtenidos y analizados a través del Discurso del Sujeto Colectivo y conteo de frecuencia, con la participación de 50 pacientes trasplantados renales.;;;;RESULTADOS:;; la muestra presentó promedio de edad de 44±12,8 años y predominancia del sexo masculino (62%). Los principales cambios positivos proporcionadas por el trasplante fueron: retorno a las actividades; libertad/independencia; bienestar y salud; fortalecimiento del yo; y estrechamiento de las relaciones interpersonales. Los estresores más citados fueron: miedo; medicación; exceso de cuidado/control; particularidades del tratamiento; y no retorno a los papeles sociales.;;;;CONCLUSIÓN:;; el trasplante renal proporcionó varios cambios positivos en la rutina del paciente, siendo el retorno a las actividades de la vida diaria la ganancia más importante, en la opinión de los participantes. En cuanto a los estresores, el miedo relacionado a la pérdida del injerto y las cuestiones relativas al medicamento inmunosupresor fueron los principales desafíos a ser enfrentados después del trasplante.;

Irinotecan- vs. Oxaliplatin-Based Doublets in KRASG12C-Mutated Metastatic Colorectal Cancer-A Multicentre Propensity-Score-Matched Retrospective Analysis

The sensitivity to chemotherapy of KRASG12C-mutated colorectal cancer has been investigated to verify whether the combination of chemotherapy plus a KRASG12C-inhibitor might become the standard of care in the near future. To this aim, the present retrospective study was designed to assess the performance of irinotecan vs. oxaliplatin in the first-line treatment of KRASG12C-mutated mCRC patients and provide support for first-line decision making. In this setting of patients treated with FOLFIRI or FOLFOX +/ bevacizumab, irinotecan and oxaliplatin were compared using a propensity-score-matched analysis. the survival superiority of irinotecan was demonstrated over oxaliplatin in KRASG12C-mutated patients, while no differences were observed in a control cohort of KRASG12D-mutated patients. this should be considered when investigating chemotherapy plus targeted agent combinations.background: KRAS(G12C)-mutated metastatic colorectal cancer (mCRC) has recently been recognized as a distinct druggable molecular entity; however, there are limited data on its sensitivity to standard chemotherapy. In the near future, the combination of chemotherapy plus a KRAS(G12C)inhibitor might become the standard of care; however, the optimal chemotherapy backbone is unknown. methods: a multicentre retrospective analysis was conducted including KRASG12C-mutated mCRC patients treated with first-line FOLFIRI or FOLFOX +/ bevacizumab. Both unmatched and propensity-score-matched analysis (PSMA) were conducted, with PSMA controlling for: previous adjuvant chemotherapy, ECOG PS, use of bevacizumab in first line, timing of metastasis appearance, time from diagnosis to first-line start, number of metastatic sites, presence of mucinous component, gender, and age. Subgroup analyses were also performed to investigate subgroup treatment-effect interactions. KRAS(G12D)-mutated patients were analysed as control. results: one hundred and four patients treated with irinotecan-(N = 47) or oxaliplatin-based (N = 57) chemotherapy were included. In the unmatched population, objective response rate (ORR) and median (m) progression-free and overall survival (mPFS and mOS) were comparable between the treatment arms. however, a late (>12 months) PFS advantage was observed with irinotecan (HR 0.62, p = 0.02). In the PSMA-derived cohort, a significant improvement with irinotecan vs. oxaliplatin was observed for both PFS and OS: 12- and 24-month PFS rates of 55% vs. 31% and 40% vs. 0% (HR 0.40, p = 0.01) and mOS 37.9 vs. 21.7 months (HR 0.45, p = 0.045), respectively. According to the subgroup analysis, interaction effects between the presence of lung metastases and treatment groups were found in terms of PFS (p for interaction = 0.08) and OS (p for interaction = 0.03), with a higher benefit from irinotecan in patients without lung metastases. no difference between treatment groups was observed in the KRASG12D-mutated cohort (N = 153). Conclusions: First-line irinotecan-based regimens provided better survival results in KRAS(G12C)-mutated mCRC patients and should be preferred over oxaliplatin. These findings should also be considered when investigating chemotherapy plus targeted agent combinations

The polymyxin B-induced transcriptomic response of a clinical, multidrug-resistant Klebsiella pneumoniae involves multiple regulatory elements and intracellular targets

Background: The emergence of multidrug-resistant Klebsiella pneumoniae is a major public health concern. Many K. pneumoniae infections can only be treated when resorting to last-line drugs such as polymyxin B (PB). However, resistance to this antibiotic is also observed, although insufficient information is described on its mode of action as well as the mechanisms used by resistant bacteria to evade its effects. We aimed to study PB resistance and the influence of abiotic stresses in a clinical K. pneumoniae strain using whole transcriptome profiling. Results: We sequenced 12 cDNA libraries of K. pneumoniae Kp13 bacteria, from two biological replicates of the original strain Kp13 (Kp13) and five derivative strains: induced high-level PB resistance in acidic pH (Kp13(pH)), magnesium deprivation (Kp13(Mg)), high concentrations of calcium (Kp13(Ca)) and iron (Kp13(Fe)), and a control condition with PB (Kp13(PolB)). Our results show the involvement of multiple regulatory loci that differentially respond to each condition as well as a shared gene expression response elicited by PB treatment, and indicate the participation of two-regulatory components such as ArcA-ArcB, which could be involved in re-routing the K. pneumoniae metabolism following PB treatment. Modules of co-expressed genes could be determined, which correlated to growth in acid stress and PB exposure. We hypothesize that polymyxin B induces metabolic shifts in K. pneumoniae that could relate to surviving against the action of this antibiotic. Conclusions: We obtained whole transcriptome data for K. pneumoniae under different environmental conditions and PB treatment. Our results supports the notion that the K. pneumoniae response to PB exposure goes beyond damaged membrane reconstruction and involves recruitment of multiple gene modules and intracellular targets.Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Lab Nacl Comp Cient, Petropolis, RJ, BrazilFiocruz MS, Ctr Pesquisas Goncalo Moniz, Salvador, BA, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Dept Internal Med, Lab Alerta,Div Infect Dis, Sao Paulo, SP, BrazilUniv Catolica Cordoba, Fac Ingn, CONICET, Cordoba, ArgentinaUniv Fed Sao Paulo, Escola Paulista Med, Dept Internal Med, Lab Alerta,Div Infect Dis, Sao Paulo, SP, BrazilFAPERJ: E-26/110.315/2014FAPESP: 2010/12891-9CAPES: 23038.010041/2013-13Web of Scienc