3D-QSAR studies of JNK1 inhibitors utilizing various alignment methods

We report our three-dimensional quantitative structure activity relationship (3D-QSAR) studies of the series of anilinopyrimidine derivatives of JNK1 inhibitors. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied using different alignment methods. The ligand-based atom-by-atom matching alignment has produced better values for CoMFA (q(2) = 0.646 and r(2) = 0.983), while in CoMSIA it has achieved only lower statistical values. The pharmacophore-based model has produced (q(2) = 0.568, r(2) = 0.938) and (q(2) = 0.670, r(2) = 0.982) for CoMFA and CoMSIA models, respectively. As the model was based on the receptor-guided alignment, all the compounds were optimized within the receptor, resulting in q(2) = 0.605 and r(2) = 0.944 for CoMFA, and q(2) = 0.587 and r(2) = 0.863 for CoMSIA. Molecular Dynamic simulation studies suggested that the generated models were consistent with the low-energy protein ligand conformation. The CoMFA and CoMSIA contour maps indicated that the substitutions of the electropositive groups in the phenyl ring, and an addition of hydrophobic groups in the pyrimidine ring, are important to enhance the activity of this series. Moreover, the virtual screening analysis against NCI database yields potentials hits, and the results obtained would be useful to synthesize selective and highly potent c-Jun N-terminal kinase 1 analogs.     

Duration-dependent growth of N1m for speech-modulated bone-conducted ultrasound

Bone-conducted ultrasound (BCU) modulated by speech sound is recognized as speech sound and activates the auditory cortex similar to audible sound. To investigate the mechanisms of perception, the effects of stimulus duration on N1m were compared among air-conducted audible speech sound (AC speech), AC speech with carrier BCU and speech-modulated BCU in eight native Japanese with normal hearing. The Japanese vowel sound /a/ was used as a stimulus with durations of 10, 15, 20, 30, 40 and 60 ms. Comparison between AC speech with and without carrier showed that the presentation of carrier had no effect on N1m evoked by AC speech. Comparison among the three conditions showed that N1m amplitude for speech-modulated BCU differed from that for the two AC speeches. Moreover, N1m amplitude growth saturated at 40 ms for speech-modulated BCU, and at 20 ms for two AC speeches. These results suggest a difference in temporal integration of N1m between speech-modulated BCU and AC speech. Considering these results, it is reasonable to conclude that N1m evoked by speech-modulated BCU is influenced mainly by the ultrasonic component rather than demodulated audible sound. Given this finding, the notion needs to be considered that the mechanisms underlying perception and recognition of speech-modulated BCU depend on the ultrasonic component to some extent.     

Functional magnetic resonance imaging as a dynamic candidate biomarker for Alzheimer's disease

During the last two decades, imaging of neural activation has become an invaluable tool for assessing the functional organization of the human brain in vivo. Due to its widespread application in neuroscience, functional neuroimaging has raised the interest of clinical researchers in its possible use as a diagnostic biomarker. A hallmark feature of many neurodegenerative diseases is their chronic non-linear dynamic and highly complex preclinical course. Neurodegenerative diseases unfold over years to decades through clinically silent and asymptomatic stages of early adaptive, compensatory to pathophysiological (i.e. actively neurodegenerative) and decompensatory mechanisms in the brain - phases that are increasingly being considered as critical for primary and secondary preventive and therapeutic measures. Emerging evidence supports the concept of a potentially fully reversible functional phase that may precede the onset of micro- and macrostructural and cognitive decline, a potentially late-stage "neurodegenerative" phase of a primary neurodegenerative disorder. Alzheimer's disease serves as an ideal model to test this hypothesis supported by the neural network model of the healthy and diseased brain. Being highly dynamic in nature, brain activation and neuronal network functional connectivity represent not only candidate diagnostic but also candidate surrogate markers for interventional trials. Potential caveats of functional imaging are critically reviewed with focus on confound variables such as altered neurovascular coupling as well as parameters related to task- and study design.     

c-Jun N terminal kinases (JNK) are activated in the brain during the pathology of experimental cerebral malaria

The aim of the present electroencephalographic (EEG) study was to investigate neuronal correlates of working memory encoding in a visuo-spatial serial delayed match-to-sample task. A rapid serial visual presentation approach was used to dissociate brain activity related to encoding of visuo-spatial targets and cortical activity evoked by suppression of distracting information. During the task EEG was recorded and steady-state visually evoked potentials (SSVEPs) were calculated. Finally, standardized low-resolution electromagnetic tomography (sLORETA) was used to determine brain regions involved in visuo-spatial working memory encoding. A distributed task-relevant network comprising right temporal, parietal, and occipital areas was identified. Results suggest that activity of this network is amplified during actual encoding of targets into visual working memory, whereas the same network is attenuated in its activation when distracting visual information should be suppressed. Left prefrontal and anterior cingulate cortices do not seem to be involved in encoding of targets but only in suppression of distracting information, likely reflecting activity of an attention-based supervisory system. These results strongly emphasise the linkage between visuo-spatial attention and working memory during amplification of selected and suppression of irrelevant information.     

Effects of stimulus field size and coherence of visual motion on cortical responses in humans: an MEG study

Among various kinds of visual motion, wide field coherent visual motion should have characteristic physiological significance regarding the relationship between the external world and us. To detect veridical visual motion in the surrounding environment, specific mechanisms are necessary to differentiate it from the wide field coherent motion due to one's own movement. To disclose whether and how the neural process of wide field coherent motion is different from that of other motions, we measured cortical responses to visual motions in humans using magnetoencephalography (MEG) manipulating both field size and coherence. Results showed that an increase in field size enhanced the response at sensors around the parieto-occipital area, and that the difference in activity between coherent and incoherent motion tended to be larger for the wide field. These findings suggest that wide field coherent and incoherent motion is detected differently at least in part in the parieto-occipital area, and suggest the neural process of wide field coherent motion could be pronouncedly tapped by a combination of field size and coherence.     

Multimodal transcranial magnetic stimulation: using concurrent neuroimaging to reveal the neural network dynamics of noninvasive brain stimulation

Since its introduction in the 1980s, Transcranial Magnetic Stimulation (TMS) has proven to be a versatile method to non-invasively study human brain function by reversibly altering ongoing neural processing. In addition, TMS has been explored as a therapeutic intervention in a number of neurological and neuropsychiatric conditions. However, our understanding of TMS-induced changes in neural activity patterns is still rather limited, particularly when it comes to changes in neural network dynamics beyond the cortical site directly targeted by TMS. In order to monitor both its local and remote neurophysiological effects, TMS has been combined with complementary neuroimaging methods that allow additional insights into how observed TMS effects at the behavioral level can be interpreted by taking into account the full scale of its impact throughout the brain. The current review provides a comprehensive overview of the existing multimodal TMS literature, covering studies in which TMS was combined with one of the three main neuroimaging modalities, namely Electroencephalography, Positron Emission Tomography, and functional Magnetic Resonance Imaging. Besides constituting a reflection of the status quo in this exciting multidisciplinary research field, this review additionally reveals both convergent and divergent observations across modalities that await corroboration or resolution, thereby further guiding ongoing basic research and providing useful constraints to optimize future clinical applications.     

B0 field inhomogeneity considerations in pseudo-continuous arterial spin labeling (pCASL): effects on tagging efficiency and correction strategy

Pseudo-continuous arterial spin labeling (pCASL) is a very powerful technique to measure cerebral perfusion, which circumvents the problems affecting other continuous arterial spin labeling schemes, such as magnetization transfer and duty cycle. However, some variability in the tagging efficiency of the pCASL technique has been reported. This article investigates the effect of B(0) field inhomogeneity on the tagging efficiency of the pCASL pulse sequence as a possible cause of this variability. Both theory and simulated data predict that the efficiency of pseudo-continuous labeling pulses can be degraded in the presence of off-resonance effects. These findings are corroborated by human in vivo measurements of tagging efficiency. On the basis of this theoretical framework, a method utilizing B(0) field map information is proposed to correct for the possible loss in tagging efficiency of the pCASL pulse sequence. The efficiency of the proposed correction method is evaluated using numerical simulations and in vivo implementation. The data show that the proposed method can effectively recover the lost tagging efficiency and signal-to-noise ratio of pCASL caused by off-resonance effects.     

Evidence for a supportive role of classical transient receptor potential 6 (TRPC6) in the exploration behavior of mice

Non-selective classical transient receptor potential (TRPC) cation channels share important roles in processes of neuronal development and function. To test the influence of TRPC6 activity on behavior, we developed a TRPC6-deficient (TRPC6^−/−) mouse model in a BALB/c genetic background. Both, TRPC6^−/− and wild-type (WT) mice were analyzed first for their general health and reflex status (modified SHIRPA protocol) and then in three different behavioral tests (marble-burying test, square open field and elevated star maze). No abnormalities were detected in the SHIRPA protocol. Most interestingly, TRPC6^−/− mice showed no significant differences in anxiety in a marble-burying test, but demonstrated reduced exploration in the square open field and the elevated star maze. Therefore, TRPC6 channel activity may play a yet unknown role for exploration behavior.     

Clinical evaluation and follow-up outcome of presurgical plan by Dextroscope: a prospective controlled study in patients with skull base tumors

Background

Patient-specific approach design, comprehensive evaluation on perioperative data, and follow-up of postoperative life quality (KPS) were carried out to evaluate the application of VR technology of Dextroscope in procedures of patients with skull base tumors.

Methods

Eighty-four patients with skull base tumors involved in this research were randomized into 2 groups (test group and control group), each with 42 patients. Before operation, image data such as MR, MRA, or CTA of head were collected and imported into the Dextroscope workstation. The detailed preoperative plans were made in the test group, but no Dextroscope plans in control group. The resection rate of tumors, preoperative evaluation including the duration of operation, total blood loss, the postoperative LOS, the number of cases with cerebrovascular injury complications in operation, and postoperative KPS of patients on discharge and the sixth month follow-up in the 2 groups were recorded and compared.

Results

The total resection rate of tumors was 83.33% in test group and 71.42% in the control group (P > .05). The total resection rate of meningioma was 86.67% in test group and 76.47% in control group. The total resection rates of trigeminal Schwannoma in the 2 groups were all 100% (P > .05). The duration of operation and the postoperative LOS of each patient were 5.25 ± 0.64 hours and 8.50 ± 1.10 days in the test group and 7.36 ± 0.87 hours and 12.50 ± 1.52 days in the control group, respectively (P < .05). Total blood loss of each patient was 456.75 ± 55.76 mL in the test group and 523.85 ± 66.78 mL in the control group (P > 05). There were 3 cases with complications of cerebral vessels injury in the test group and 7 cases in the control group (P < .05). During follow-up, KPS of patients in the test group on discharge (85.75 ± 9.68) was significantly superior to that in the control group (81.66 ± 9.24; P < .05). The KPS of patients on the sixth-month follow-up in the test group was 92.35 ± 9.95, which was significantly superior to that in the control group (85.6 ± 9.34; P < .05). Karnofsky performance scores of patients in the test group improved significantly from discharge to the sixth month after procedure (P < .05), whereas there were adverse results in the test group (P < .05). The 2 cases with CSF leakage were cured completely.

Conclusion

The preoperative plans with VR technology in patients with skull base tumor or CSF leakage operations can help certain the diagnosis, individually locate the position of skull base lesions, and design patient-specific approach, which also facilitate to shorten operation duration and the postoperative LOS, reduce total blood loss and injury of vessels in operation, and improve the postoperative KPS.     

Biophysical stimulation in osteonecrosis of the femoral head

Osteonecrosis of the femoral head is the endpoint of a disease process that results from insufficient blood flow and bone-tissue necrosis, leading to joint instability, collapse of the femoral head, arthritis of the joint, and total hip replacement. Pain is the most frequent clinical symptom. Both bone tissue and cartilage suffer when osteonecrosis of the femoral head develops. Stimulation with pulsed electromagnetic fields (PEMFs) has been shown to be useful for enhancing bone repair and for exerting a chondroprotective effect on articular cartilage. Two Italian studies on the treatment of avascular necrosis of the femoral head with PEMFs were presented in this review. In the first study, 68 patients suffering from avascular necrosis of the femoral head were treated with PEMFs in combination with core decompression and autologous bone grafts. The second one is a retrospective analysis of the results of treatment with PEMFs of 76 hips in 66 patients with osteonecrosis of the femoral head. In both studies clinical information and diagnostic imaging were collected at the beginning of the treatment and at the time of follow up. Statistical analysis was performed using chi-square test. Both authors hypothesize that the short-term effect of PEMF stimulation may be to protect the articular cartilage from the catabolic effect of inflammation and subchondral bone-marrow edema. The long-term effect of PEMF stimulation may be to promote osteogenic activity at the necrotic area and prevent trabecular fracture and subchondral bone collapse. PEMF stimulation represents an important therapeutic opportunity to resolve the Ficat stage-I or II disease or at least to delay the time until joint replacement becomes necessary.