Development of indole/indazole-aminopyrimidines as inhibitors of c-Jun N-terminal kinase (JNK): Optimization for JNK potency and physicochemical properties

A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC₅₀ of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.     

Proteomic and physiological analyses reveal detoxification and antioxidation induced by Cd stress in Kandelia candel roots

The heavy metal Cadmium (Cd), added to the water bodies through weathering of rocks and human activities, constitutes one of the major environmental pollutants toxic to plants. This study examines the proteome changes in roots of actively growing Kandelia candel (L.) Druce when challenged with Cd. This mangrove-like species proliferates in estuaries and bays and is a potential choice for phytoremediation of Cd. A total of 53 proteins were up- or down-regulated following a short-term Cd treatment. The identities of the differentially expressed proteins were determined by MALDI-TOF/TOF. Approximately half of the up-regulated proteins are involved in oxidative response, including antioxidant enzymes, enzymes required for glutathione biosynthesis, enzymes in TCA and PPP cycles for generating ATP, NADH and NADPH. These results support the prediction that a prompt antioxidative response is necessary for the reduction of the oxidative stress caused by Cd and set the stage for further investigating of Cd up-regulated proteins in Kandelia candel.     

A retrospective analysis of 140 patients with giant cell tumor in the extremity: A multicenter study based on four hospitals in South China

Background: Update reports are rarely available regarding the bone giant cell tumors (GCTs) in the extremity in Chinese people. The aim of this study was to review the epidemiological characteristics of bone GCT in the extremity based on the clinical data from four hospitals in South China. Methods: We searched medical electronic records from January 2001 to December 2011 in four hospitals in South China to identify patients with definite diagnosis of extremity GCT. Epidemiological data including gender, tumor site, age at the time of first diagnosis, local recurrence and pulmonary metastasis were collected and analyzed statistically. Differences between-genders were particularly analyzed regarding first diagnosis age, tumor site, local recurrence and pulmonary metastasis. T-test and Chi-square test were used for continuous and dichotomous variables, respectively. Results: A total of 140 GCT patients (87 males and 53 females) were identified. The gender ratio was 1.64 for a male predominance. GCTs were mostly located around the knee (67 cases). 92 patients were in their 20s to 40s upon first diagnosis. The average age at the time of first diagnosis for all was 30.49 years, 30.76 years for males and 30.06 years for females (P = 0.757). GCT recurred locally in 50 patients (26 males and 24 females) with no gender difference (P = 0.065). The average interval from first surgery to local recurrence was 21.42 months. Pulmonary metastasis was found in 11 patients (8 males and 3 females) also with no gender difference (P = 0.667). The average interval from first diagnosis to metastasis was 36.45 months. Conclusions: Extremity GCT may have a male predominance in Chinese population and mostly occur at 20–40 years of age and around the knee. Follow-ups for GCT patients should be carried on for at least 3 years after primary surgery according to the average intervals for possible local recurrence and pulmonary metastasis.     

Affective Computing and the Impact of Gender and Age

Affective computing aims at the detection of users’ mental states, in particular, emotions and dispositions during human-computer interactions. Detection can be achieved by measuring multimodal signals, namely, speech, facial expressions and/or psychobiology. Over the past years, one major approach was to identify the best features for each signal using different classification methods. Although this is of high priority, other subject-specific variables should not be neglected. In our study, we analyzed the effect of gender, age, personality and gender roles on the extracted psychobiological features (derived from skin conductance level, facial electromyography and heart rate variability) as well as the influence on the classification results. In an experimental human-computer interaction, five different affective states with picture material from the International Affective Picture System and ULM pictures were induced. A total of 127 subjects participated in the study. Among all potentially influencing variables (gender has been reported to be influential), age was the only variable that correlated significantly with psychobiological responses. In summary, the conducted classification processes resulted in 20% classification accuracy differences according to age and gender, especially when comparing the neutral condition with four other affective states. We suggest taking age and gender specifically into account for future studies in affective computing, as these may lead to an improvement of emotion recognition accuracy.     

A bispecific antibody effectively neutralizes all four serotypes of dengue virus by simultaneous blocking virus attachment and fusion

Although dengue virus (DENV) infection severely threatens the health of humans, no specific antiviral drugs are currently approved for clinical use against DENV infection. Attachment and fusion are 2 critical steps for the flavivirus infection, and the corresponding functional epitopes are located at E protein domain III (E-DIII) and domain II (E-DII), respectively. Here, we constructed a bispecific antibody (DVD-1A1D-2A10) based on the 2 well-characterized anti-DENV monoclonal antibodies 1A1D-2 (1A1D) and 2A10G6 (2A10). The 1A1D antibody binds E-DIII and can block the virus attaching to the cell surface, while the 2A10 antibody binds E-DII and is able to prevent the virus from fusing with the endosomal membrane. Our data showed that DVD-1A1D-2A10 retained the antigen-binding activity of both parental antibodies. Importantly, it was demonstrated to be significantly more effective at neutralizing DENV than its parental antibodies both in vitro and in vivo, even better than the combination of them. To eliminate the potential antibody-dependent enhancement (ADE) effect, this bispecific antibody was successfully engineered to prevent Fc-γ-R interaction. Overall, we generated a bispecific anti-DENV antibody targeting both attachment and fusion stages, and this bispecific antibody broadly neutralized all 4 serotypes of DENV without risk of ADE, suggesting that it has great potential as a novel antiviral strategy against DENV.     

Augmentation of Autoantibodies by Helicobacter pylori in Parkinson’s Disease Patients May Be Linked to Greater Severity

Parkinson''s disease (PD) is the second most common chronic and progressive neurodegenerative disorder. Its etiology remains elusive and at present only symptomatic treatments exists. Helicobacter pylori chronically colonizes the gastric mucosa of more than half of the global human population. Interestingly, H. pylori positivity has been found to be associated with greater of PD motor severity. In order to investigate the underlying cause of this association, the Sengenics Immunome protein array, which enables simultaneous screening for autoantibodies against 1636 human proteins, was used to screen the serum of 30 H. pylori-seropositive PD patients (case) and 30 age- and gender-matched H. pylori-seronegative PD patients (control) in this study. In total, 13 significant autoantibodies were identified and ranked, with 8 up-regulated and 5 down-regulated in the case group. Among autoantibodies found to be elevated in H. pylori-seropositive PD were included antibodies that recognize Nuclear factor I subtype A (NFIA), Platelet-derived growth factor B (PDGFB) and Eukaryotic translation initiation factor 4A3 (eIFA3). The presence of elevated autoantibodies against proteins essential for normal neurological functions suggest that immunomodulatory properties of H. pylori may explain the association between H. pylori positivity and greater PD motor severity.     

Aqueous Angiography: Real-Time and Physiologic Aqueous Humor Outflow Imaging

Purpose

Trabecular meshwork (TM) bypass surgeries attempt to enhance aqueous humor outflow (AHO) to lower intraocular pressure (IOP). While TM bypass results are promising, inconsistent success is seen. One hypothesis for this variability rests upon segmental (non-360 degrees uniform) AHO. We describe aqueous angiography as a real-time and physiologic AHO imaging technique in model eyes as a way to simulate live AHO imaging.

Methods

Pig (n = 46) and human (n = 6) enucleated eyes were obtained, orientated based upon inferior oblique insertion, and pre-perfused with balanced salt solution via a Lewicky AC maintainer through a 1mm side-port. Fluorescein (2.5%) was introduced intracamerally at 10 or 30 mm Hg. With an angiographer, infrared and fluorescent (486 nm) images were acquired. Image processing allowed for collection of pixel information based on intensity or location for statistical analyses. Concurrent OCT was performed, and fixable fluorescent dextrans were introduced into the eye for histological analysis of angiographically active areas.

Results

Aqueous angiography yielded high quality images with segmental patterns (p<0.0001; Kruskal-Wallis test). No single quadrant was consistently identified as the primary quadrant of angiographic signal (p = 0.06–0.86; Kruskal-Wallis test). Regions of high proximal signal did not necessarily correlate with regions of high distal signal. Angiographically positive but not negative areas demonstrated intrascleral lumens on OCT images. Aqueous angiography with fluorescent dextrans led to their trapping in AHO pathways.

Conclusions

Aqueous angiography is a real-time and physiologic AHO imaging technique in model eyes.