Further insights into the antinociceptive potential of a peptide disrupting the N-type calcium channel-CRMP-2 signaling complex

The N-type voltage-gated calcium channel (Cav 2.2) has gained immense prominence in the treatment of chronic pain. While decreased channel function is ultimately anti-nociceptive, directly targeting the channel can lead to multiple adverse side effects. Targeting modulators of channel activity may facilitate improved analgesic properties associated with channel block and a broader therapeutic window. A novel interaction between Cav 2.2 and collapsin response mediator protein 2 (CRMP-2) positively regulates channel function by increasing surface trafficking. We recently identified a CRMP-2 peptide (TAT-CBD3), which effectively blocks this interaction, reduces or completely reverses pain behavior in a number of inflammatory and neuropathic models. Importantly, TAT-CBD3 did not produce many of the typical side effects often observed with Cav 2.2 inhibitors. Notably chronic pain mechanisms offer unique challenges as they often encompass a mix of both neuropathic and inflammatory elements, whereby inflammation likely causes damage to the neuron leading to neuropathic pain, and neuronal injury may produce inflammatory reactions. To this end, we sought to further disseminate the ability of TAT-CBD3 to alter behavioral outcomes in two additional rodent pain models. While we observed that TAT-CBD3 reversed mechanical hypersensitivity associated with a model of chronic inflammatory pain due to lysophosphotidylcholine-induced sciatic nerve focal demyelination (LPC), injury to the tibial nerve (TNI) failed to respond to drug treatment. Moreover, a single amino acid mutation within the CBD3 sequence demonstrated amplified Cav 2.2 binding and dramatically increased efficacy in an animal model of migraine. Taken together, TAT-CBD3 potentially represents a novel class of therapeutics targeting channel regulation as opposed to the channel itself.     

Lactate promotes glutamine uptake and metabolism in oxidative cancer cells

Oxygenated cancer cells have a high metabolic plasticity as they can use glucose, glutamine and lactate as main substrates to support their bioenergetic and biosynthetic activities. Metabolic optimization requires integration. While glycolysis and glutaminolysis can cooperate to support cellular proliferation, oxidative lactate metabolism opposes glycolysis in oxidative cancer cells engaged in a symbiotic relation with their hypoxic/glycolytic neighbors. However, little is known concerning the relationship between oxidative lactate metabolism and glutamine metabolism. Using SiHa and HeLa human cancer cells, this study reports that intracellular lactate signaling promotes glutamine uptake and metabolism in oxidative cancer cells. It depends on the uptake of extracellular lactate by monocarboxylate transporter 1 (MCT1). Lactate first stabilizes hypoxia-inducible factor-2α (HIF-2α), and HIF-2α then transactivates c-Myc in a pathway that mimics a response to hypoxia. Consequently, lactate-induced c-Myc activation triggers the expression of glutamine transporter ASCT2 and of glutaminase 1 (GLS1), resulting in improved glutamine uptake and catabolism. Elucidation of this metabolic dependence could be of therapeutic interest. First, inhibitors of lactate uptake targeting MCT1 are currently entering clinical trials. They have the potential to indirectly repress glutaminolysis. Second, in oxidative cancer cells, resistance to glutaminolysis inhibition could arise from compensation by oxidative lactate metabolism and increased lactate signaling.     

Mining of expressed sequence tag libraries of cacao for microsatellite markers using five computational tools

Expressed sequence tags (ESTs) provide researchers with a quick and inexpensive route for discovering new genes, data on gene expression and regulation, and also provide genic markers that help in constructing genome maps. Cacao is an important perennial crop of humid tropics. Cacao EST sequences, as available in the public domain, were downloaded and made into contigs. Microsatellites were located in these ESTs and contigs using five softwares (MISA, TRA, TROLL, SSRIT and SSR primer). MISA gave maximum coverage of SSRs in cacao ESTs and contigs, although TRA was able to detect higher order (>5-mer) repeats. The frequency of SSRs was one per 26.9 kb in the known set of ESTs. One-third of the repeats in EST-contigs were found to be trimeric. A few rare repeats like 21-mer repeat were also located. A/T repeats were most abundant among the mononucleotide repeats and the AG/GA/TC/CT type was the most frequent among dimerics. Flanking primers were designed using Primer3 program and verified experimentally for PCR amplification. The results of the study are made available freely online database (). Seven primer pairs amplified genomic DNA isolated from leaves were used to screen a representative set of 12 accessions of cacao.     

Germanium tetra(tertiary butoxide): Synthesis, structure and its utility as a precursor for the preparation of europium doped germanium oxide nanoparticles

Germanium tetra(tertiary butoxide), [Ge(O^tBu)₄], has been prepared by the reaction of GeCl₄ with KOBu^t in benzene. It is a monomeric crystalline solid having a distorted tetrahedral configuration, defined by the coordination of four OBu^t groups around germanium atom. The TG analysis showed that the compound is thermally stable and volatilizes at around 130 °C. Europium doped and un-doped germanium oxide nanoparticles were prepared based on the urea hydrolysis of Ge(O^tBu)₄/Eu(OOCCH₃)₃ in ethylene glycol medium at 150 °C followed by heating the resulting product at 750 °C. The nanoparticles were characterized by XRD, TEM and PL measurements. The europium doped nanoparticles, which were nearly monodispersed (∼30 nm), showed luminescence and the Eu³⁺ ions were occupying the surface of the GeO₂ nanoparticles.     

A Direct Brain-to-Brain Interface in Humans

We describe the first direct brain-to-brain interface in humans and present results from experiments involving six different subjects. Our non-invasive interface, demonstrated originally in August 2013, combines electroencephalography (EEG) for recording brain signals with transcranial magnetic stimulation (TMS) for delivering information to the brain. We illustrate our method using a visuomotor task in which two humans must cooperate through direct brain-to-brain communication to achieve a desired goal in a computer game. The brain-to-brain interface detects motor imagery in EEG signals recorded from one subject (the “sender”) and transmits this information over the internet to the motor cortex region of a second subject (the “receiver”). This allows the sender to cause a desired motor response in the receiver (a press on a touchpad) via TMS. We quantify the performance of the brain-to-brain interface in terms of the amount of information transmitted as well as the accuracies attained in (1) decoding the sender’s signals, (2) generating a motor response from the receiver upon stimulation, and (3) achieving the overall goal in the cooperative visuomotor task. Our results provide evidence for a rudimentary form of direct information transmission from one human brain to another using non-invasive means.     

Aurora Kinases as Druggable Targets in Pediatric Leukemia: Heterogeneity in Target Modulation Activities and Cytotoxicity by Diverse Novel Therapeutic Agents

Leukemia is the most common pediatric malignancy, constituting more than 30% of all childhood cancers. Although cure rates have improved greatly, approximately one in five children relapse and poor survival rates post relapse remain a challenge. Given this, more effective and innovative therapeutic strategies are needed in order to improve prognosis. Aurora kinases, a family of serine/threonine kinases essential for the regulation of several mitotic processes, have been identified as potential targets for cancer therapeutics. Elevated expression of Aurora kinases has been demonstrated in several malignancies and is associated with aberrant mitotic activity, aneuploidy and alterations in chromosomal structure and genome instability. Based on this rationale, a number of small molecule inhibitors have been formulated and advanced to human studies in the recent past. A comparative analysis of these agents in cytotoxicity and target modulation analyses against a panel of leukemia cells provides novel insights into the unique mechanisms and codependent activity pathways involved in targeting Aurora kinases, constituting a distinctive preclinical experimental framework to identify appropriate agents and combinations in future clinical studies.     

Maternal hormonal interventions as a risk factor for Autism Spectrum Disorder: An epidemiological assessment from India

Globalization and women empowerment have led to stressful life among Indian women. This stress impairs women’s hormonal makeup and menstrual cycle, leading to infertility. National Family Health Survey-3 (NFHS-3) reports a decline in fertility status in India, indicating a rise in various infertility treatments involving hormonal interventions. No studies are available from India on the risk association link between maternal hormonal treatments and ASD. Hence, this study explores the association of maternal hormonal interventions with risk for ASD. Parents of 942 children (471 ASD and 471 controls) across 9 cities in India participated in the questionnaire-based study. The questionnaire was pilot tested and validated for its content and reliability as a psychometric instrument. Data collection was done at 70 centres through direct interaction with parents and with the help of trained staff. Statistical analysis of data was carried out using SAS 9.1.3. Out of the 471 ASD cases analysed, 58 mothers had undergone hormonal interventions (12.3%) while there were only 22 mothers among controls who underwent hormonal interventions (4.6%). According to logistic regression analysis maternal hormonal intervention (OR=2.24) was a significant risk factor for ASD.     

Cutaneous Injury-Related Structural Changes and Their Progression following Topical Nitrogen Mustard Exposure in Hairless and Haired Mice

To identify effective therapies against sulfur mustard (SM)-induced skin injuries, various animals have been used to assess the cutaneous pathology and related histopathological changes of SM injuries. However, these efforts to establish relevant skin injury endpoints for efficacy studies have been limited mainly due to the restricted assess of SM. Therefore, we employed the SM analog nitrogen mustard (NM), a primary vesicating and bifunctional alkylating agent, to establish relevant endpoints for efficient efficacy studies. Our published studies show that NM (3.2 mg) exposure for 12–120 h in both the hairless SKH-1 and haired C57BL/6 mice caused clinical sequelae of toxicity similar to SM exposure in humans. The NM-induced cutaneous pathology-related structural changes were further analyzed in this study and quantified morphometrically (as percent length or area of epidermis or dermis) of skin sections in mice showing these lesions. H&E stained skin sections of both hairless and haired mice showed that NM (12–120 h) exposure caused epidermal histopathological effects such as increased epidermal thickness, epidermal-dermal separation, necrotic/dead epidermis, epidermal denuding, scab formation, parakeratosis (24–120 h), hyperkeratosis (12–120 h), and acanthosis with hyperplasia (72–120 h). Similar NM exposure in both mice caused dermal changes including necrosis, edema, increase in inflammatory cells, and red blood cell extravasation. These NM-induced cutaneous histopathological features are comparable to the reported lesions from SM exposure in humans and animal models. This study advocates the usefulness of these histopathological parameters observed due to NM exposure in screening and optimization of rescue therapies against NM and SM skin injuries.