The multifaceted role of Wnt canonical signalling in neurogenesis, neuroinflammation, and hyperexcitability in mesial temporal lobe epilepsy.

Epilepsy is a neurological disorder characterised by unprovoked, repetitive seizures caused by abnormal neuronal firing. The Wnt/ß-Catenin signalling pathway is involved in seizure-induced neurogenesis, aberrant neurogenesis, neuroinflammation, and hyperexcitability associated with epileptic disorder. Wnt/ß-Catenin signalling is crucial for early brain development processes including neuronal patterning, synapse formation, and N-methyl-d-aspartate receptor (NMDAR) regulation. Disruption of molecular networks such as Wnt/ß-catenin signalling in epilepsy could offer encouraging anti-epileptogenic targets. So, with a better understanding of the canonical Wnt/-Catenin pathway, we highlight in this review the important elements of Wnt/-Catenin signalling specifically in Mesial Temporal Lobe Epilepsy (MTLE) for potential therapeutic targets.

Mean performances, character associations and multi-environmental evaluation of chilli landraces in north western Himalayas.

Even though many varieties have been recommended across agro-climate zones of Himachal Pradesh, yet the information on stability is lacking in this State. Hence, the present investigation was carried out to identify high yielding stable genotypes among various pre-adapted landraces. The material consists of 20 chilli landraces including check i.e. DKC-8. The experiment was laid out in a RCBD. The data were recorded and analyzed to work out mean performances and the inferences were drawn for parameters of variability, correlation coefficients, path coefficients and stability analysis. As per mean performances, CS7 and CS9 were earliest in flowering, CS13 is earliest in days to ripe maturity, CS10 had highest plant height and CS9 had highest average fruit weight and ripe fruit yield plant-1. High PCV and GCV were recorded for ripe fruit yield plant-1. Heritability and genetic advance were recorded maximum for plant height in summer seasons and were recorded maximum for number of ripe fruits plant-1 in winter season. Correlation coefficients showed that number of ripe fruits plant-1 and average ripe fruit weight were positively and significantly correlated with ripe fruit yield plant-1. Path coefficient analysis in summer and winter seasons showed that average ripe fruit weight had the highest positive direct effect on ripe fruit yield plant-1. The pooled data over environments were analyzed to estimate the interaction effects between genotypes × environment. The mean sum of squares due to genotypes, environments and genotypes × environment interaction were significant for all the characteristics. CS1, CS3, CS6, CS10, CS13, CS15 were adapted to all environments, CS7 and CS9 were specifically adapted to favourable environment and CS2 was specifically adapted to unfavorable environment for 50% flowering, landraces CS1, CS2 and CS3were well adapted to all environments for ripe maturity whereas landraces CS6, CS10 and CS19 were well adapted to all environment for number of ripe fruit and ripe fruit yield.

Bio-piezoelectric phenylalanine-αß-dehydrophenylalanine nanotubes as potential modalities for combinatorial electrochemotherapy in glioma cells.

Bio-piezoelectric materials are endowed with characteristic features such as non-invasiveness, small energy attenuation and deep tissue penetrability. Thus, they have the ability to serve as both diagnostic and therapeutic modalities for targeting and treating various dreaded disorders scourging mankind. Herein, piezoelectric nanotubes derived from a modified amino acid-containing dipeptide, phenylalanine-αß-dehydrophenylalanine (Phe-ΔPhe; FΔF), possessing acoustic stimulation-triggered reactive oxygen species (ROS) generating ability, were employed and projected for achieving a piezo-active response enabled anti-cancer effect in glioma cells. A model anti-cancer drug doxorubicin (Dox) was also loaded into the nanotubes and the combined system depicted enhanced ROS production and cell killing under an acoustically developed piezo-catalytic environment. Cellular level assessment studies demonstrated that the dipeptide based piezoelectric nanotubes could lead to an increase in the cellular Ca2+ ion concentration, further inducing ROS-triggered cytotoxicity accompanied by high therapeutic efficacy in C6 glioma cells. Overall, our structures have the uniqueness of serving as acoustic stimulus-driven, wireless, and non-invasive electro-chemotherapeutic agents for enabling heightened cancer cell killing and may complement other chemotherapeutic modalities for treating the disease.

Multiple Damage Detection in PZT Sensor Using Dual Point Contact Method.

Lead Zirconate Titanate (PZT) is used to make ultrasound transducers, sensors, and actuators due to its large piezoelectric coefficient. Several micro-defects develop in the PZT sensor due to delamination, corrosion, huge temperature fluctuation, etc., causing a decline in its performance. It is thus necessary to identify, locate, and quantify the defects. Non-Destructive Structural Health Monitoring (SHM) is the most optimal and economical evaluation method. Traditional ultrasound SHM techniques have a huge impedance mismatch between air and solid material, and most of the popular signal processing methods define time series signals in only one domain, which provides sub-optimal results for non-stationary signals. Thus, to improve the accuracy of detection, the point contact excitation and detection method is implemented to determine the interaction of ultrasonic waves with micro-scale defects in the PZT. The signal generated from this method being non-stationary in nature, it requires signal processing with changeable resolutions at different times and frequencies. The Haar Discrete Wavelet Transformation (DWT) is applied to the time series data obtained from the coulomb coupling setup. Using the above process, defects up to 100 µm in diameter could be successfully distinguished.

Ultrashort Peptide-Based Hydrogel for the Healing of Critical Bone Defects in Rabbits.

The use of hydrogels as scaffolds for three-dimensional (3D) cell growth is an active area of research in tissue engineering. Herein, we report the self-assembly of an ultrashort peptide, a tetrapeptide, Asp-Leu-IIe-IIe, the shortest peptide sequence from a highly fibrillogenic protein TDP-43, into the hydrogel. The hydrogel was mechanically strong and highly stable, with storage modulus values in MPa ranges. The hydrogel supported the proliferation and successful differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) in its matrix as assessed by cell viability, calcium deposition, alkaline phosphatase (ALP) activity, and the expression of osteogenic marker gene studies. To check whether the hydrogel supports 3D growth and regeneration in in vivo conditions, a rabbit critical bone defect model was used. Micro-computed tomography (CT) and X-ray analysis demonstrated the formation of mineralized neobone in the defect areas, with significantly higher bone mineralization and relative bone densities in animals treated with the peptide hydrogel compared to nontreated and matrigel treatment groups. The ultrashort peptide-based hydrogel developed in this work holds great potential for its further development as tissue regeneration and/or engineering scaffolds.

Conformationally Restricted Dipeptide-Based Nanoparticles for Delivery of siRNA in Experimental Liver Cirrhosis.

Liver cirrhosis is a major health problem with multiple associated complications. The presently available drug delivery systems showed moderate site-specific delivery of antifibrotic molecules to the diseased liver; therefore, research on more effective and selective delivery systems in the context of liver cirrhosis remains a necessity in clinical investigation. The aim of the present study was to develop a peptide-based targeted nanocarrier to deliver an oligonucleotide to the hepatic sinusoidal and perivascular regions of the cirrhotic liver. We have synthesized and characterized a conformationally restricted targeted pentapeptide (RΔFRGD), which contains an unnatural amino acid, α,ß-dehydrophenylalanine (ΔF). The RΔFRGD self-assembled into spherical nanoparticles (NPs) and was characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Next, we investigated the delivery potential of the pentapeptide-based NPs to make a stable complex with a well-established small interference RNA and studied its site-specific delivery in experimental liver cirrhosis. We used siNR4A1 of the orphan nuclear receptor 4A1 (NR4A1), a well-known regulatory checkpoint for controlling liver fibrosis. Peptide NPs and their complex with siNR4A1 showed high biocompatibility against various mammalian cell lines. Hepatic tissue biodistribution analysis illustrated that targeted NPs predominantly accumulated in the cirrhotic liver compared to normal rats, specifically in sinusoidal and perivascular areas. A significant downregulation of the NR4A1 mRNA expression (-70%) andlower levels of the NR4A1/GAPDH ratio (-55%) were observed in the RΔFRGD-siNR4A1 nanocomplex-treated group in comparison to the RΔFRGD-vehicle group (RΔFRGD-Veh) at the gene and protein levels, respectively. In addition, in vivo inhibition of NR4A1 produced a significant aggravation in hepatic fibrosis compared with siRNA-vehicle-treated rats (+41% in the MT stain). The novel pentapeptide-based targeted delivery system can be further evaluated and validated for therapeutic purposes in various pathological conditions.

Chemically Modified Dipeptide Based Hydrogel Supports Three-Dimensional Growth and Functions of Primary Hepatocytes.

A huge shortage of organ donors, particularly in the case of liver, has necessitated the development of alternative therapeutic strategies. Primary hepatocytes (pHCs) transplantation has made a considerable transition from bench to bedside, but the short-term viability and functionality of pHCs in in vitro limit their use for clinical applications. Different cell culture strategies are required to maintain the proliferation of pHCs for extended periods. Here, we described the formation of a hybrid scaffold based on a modified dipeptide for the culture of pHCs. First, the dipeptide (Dp), isoleucine-α,ß-dehydrophenylalanine (IΔF) was synthesized, purified, and fully characterized. IΔF readily formed a highly stable hydrogel, which was also characterized by CD, TEM, and thioflavin T assay. The addition of soluble liver extracellular matrix (sLEM) to the dipeptide readily formed a hybrid scaffold that was characterized by TEM, and its mechanical strength was determined by rheology experiments. The hybrid scaffold was translucent, biocompatible, and proteolytically stable and, with its mechanical strength, closely mimicked that of the native liver. LEM1-Dp matrix exhibited high biocompatibility in the readily available adherent liver cell line Huh7 and primary rat hepatocyte cells (pHCs). pHCs cultured on LEM1-Dp matrix also maintained significantly higher cell viability and an escalated expression of markers related to the hepatocytes such as albumin as compared to that observed in cells cultured on collagen type I (Col I)-coated substrate plate (col-TCTP). Z-stacking of confocal laser microscopy's volume view clearly indicated pHCs seeded on top of the hydrogel matrix migrated toward the Z direction showing 3D growth. Our results indicated that low molecular weight dipeptide hydrogel along with sLEM can resemble biomimetic 3D-like microenvironments for improved pHCs proliferation, differentiation, and function. This hybrid scaffold is also easy to scale up, which makes it suitable for several downstream applications of hepatocytes, including drug development, pHCs transplantation, and liver regeneration.

Task-independent metrics of computational hardness predict human cognitive performance.

The survival of human organisms depends on our ability to solve complex tasks in the face of limited cognitive resources. However, little is known about the factors that drive the complexity of those tasks. Here, building on insights from computational complexity theory, we quantify the computational hardness of cognitive tasks using a set of task-independent metrics related to the computational resource requirements of individual instances of a task. We then examine the relation between those metrics and human behavior and find that they predict both time spent on a task as well as accuracy in three canonical cognitive tasks. Our findings demonstrate that performance in cognitive tasks can be predicted based on generic metrics of their inherent computational hardness.

Conformationally restricted, dipeptide-based, self-assembled nanoparticles for efficient vancomycin delivery.

Aim: Emergence of vancomycin (Van) resistance, and usage of its higher dose and short half-life are posing a serious concern. Slow and sustained release of Van using a nanodelivery system may overcome these problems. Materials & methods: Arginine-α,ß-dehydrophenylalanine (RΔF) was synthesized using solution-phase synthesis which self-assembled into nanospheres. Van was entrapped in the nanoparticles (NPs). In vitro and in vivo efficacy of Van-RΔF was determined using broth microdilution and the mouse thigh infection model, respectively. Results & conclusion: Van-RΔF NPs efficiently inhibited bacterial growth (Staphylococcus aureus), while Van alone showed limited growth inhibition in in vitro. Intravenous administration of Van-RΔF in mice with bacterial thigh infection showed enhanced efficacy (double) compared with Van alone, which indicates its high potential for further development.

Currently, microbial infections have become the most prevalent threat to human health. In the past few decades, researchers have tried different strategies to deal with these infections by developing new antimicrobial agents and/or improving the efficacy of already available antimicrobial agents. Controlled delivery of antimicrobial agents using nanosized vehicle systems has shown great promise in antimicrobial therapy. The authors have developed an ultrashort, modified, peptide-based nanoparticle system that can load vancomycin and release it in a controlled and sustained manner. Unlike other polymer-based nanoparticles, these dipeptide-based nanoparticles are easy to synthesize and highly biocompatible in nature. Vancomycin delivered via these peptide-based nanoparticles showed higher antibacterial activity than the drug alone. These results clearly indicated the high potential of this nanoformulation for further development as a delivery vehicle system for efficient antimicrobial therapy.

Intelligent Transport System Using Time Delay-Based Multipath Routing Protocol for Vehicular Ad Hoc Networks.

During the last decade, the research on Intelligent Transportation System (ITS) has improved exponentially in real-life scenarios to provide optimized transport network performance. It is a matter of importance that alert messages are delivered promptly to prevent vehicular traffic problems. The fact is an ITS system per se could be a part of a vehicular ad hoc network (VANET) which is an extension of a wireless network. In all sorts of wireless ad hoc networks, the network topology is subjected to change due to the mobility of network nodes; therefore, an existing explored route between two nodes could be demolished in a minor fraction of time. When it comes to the VANETs, the topology likely changes due to the high velocity of nodes. On the other hand, time is a crucial factor playing an important role in message handling between the network's nodes. In this paper, we propose Time delay-based Multipath Routing (TMR) protocol that effectively identifies an optimized path for packet delivery to the destination vehicle with a minimal time delay. Our algorithm gives a higher priority to alert messages compared to normal messages. It also selects the routes with the short round-trip time (RTT) within the RTT threshold. As a result, our algorithm would realize two goals. Firstly, it would speed up the data transmission rate and deliver data packets, particularly warning messages, to the destination vehicle promptly and therefore avoid vehicular problems such as car accidents. Secondly, the TMR algorithm reduces the data traffic load, particularly of the normal messages, to alleviate the pressure on the network and therefore avoids network congestion and data collisions. This, in turn, lessens the packets' retransmissions. To demonstrate the effectiveness of the proposed protocol, the TMR has been compared with the other protocols such as AOMDV, FF-AOMDV, EGSR, QMR, and ISR. Simulation results demonstrate that our proposed protocol proves its excellent performance compared to other protocols.

Transferring cognitive talent across domains to reduce the disposition effect in investment.

We consider Theory of Mind (ToM), the ability to correctly predict the intentions of others. To an important degree, good ToM function requires abstraction from one's own particular circumstances. Here, we posit that such abstraction can be transferred successfully to other, non-social contexts. We consider the disposition effect, which is a pervasive cognitive bias whereby investors, including professionals, improperly take their personal trading history into account when deciding on investments. We design an intervention policy whereby we attempt to transfer good ToM function, subconsciously, to personal investment decisions. In a within-subject repeated-intervention laboratory experiment, we record how the disposition effect is reduced by a very significant 85%, but only for those with high scores on the social-cognitive dimension of ToM function. No such transfer is observed in subjects who score well only on the social-perceptual dimension of ToM function. Our findings open up a promising way to exploit cognitive talent in one domain in order to alleviate cognitive deficiencies elsewhere.

Delivery of a Cancer-Testis Antigen-Derived Peptide Using Conformationally Restricted Dipeptide-Based Self-Assembled Nanotubes.

Use of tumor-associated antigens for cancer immunotherapy is limited due to their poor in vivo stability and low cellular uptake. Delivery of antigenic peptides using synthetic polymer-based nanostructures has been actively pursued but with limited success. Peptide-based nanostructures hold much promise as delivery vehicles due to their easy design and synthesis and inherent biocompatibility. Here, we report self-assembly of a dipeptide containing a non-natural amino acid, α,ß-dehydrophenylalanine (ΔF), into nanotubes, which efficiently entrapped a MAGE-3-derived peptide (M3). M3 entrapped in F-ΔF nanotubes was more stable to a nonspecific protease treatment and both F-ΔF and F-ΔF-M3 showed no cellular toxicity for four cancerous and noncancerous cell lines used. F-ΔF-M3 showed significantly higher cellular uptake in RAW 267.4 macrophage cells compared to M3 alone and also induced in vitro maturation of dendritic cells (DCs). Immunization of mice with F-ΔF-M3 selected a higher number of IFN-γ secreting CD8+ T cells and CD4+ T compared to M3 alone. On day 21, a tumor growth inhibition ratio (TGI, %) of 41% was observed in a murine melanoma model. These results indicate that F-ΔF nanotubes are highly biocompatible, efficiently delivered M3 to generate cytotoxic T lymphocytes responses, and able to protect M3 from degradation under in vivo conditions. The F-ΔF dipeptide-based nanotubes may be considered as a good platform for further development as delivery agents.

Mass spectrometry-based lipidomic analysis reveals altered lipid profile in brain tissues resected from patients with focal cortical dysplasia (FCD).

Focal cortical dysplasia (FCD) is a common pathology responsible for drug-resistant epilepsy (DRE). Failure to precisely localize the epileptogenic zones (EZs) is a major reason for poor surgical outcome in FCD. Currently, there are no molecular or cellular biomarkers available which can aid in defining the EZs in FCD. Phospholipid alterations between healthy and malignant tumor tissues are reported and have been used for marking tumor margins. In this study, we utilize liquid chromatography and tandem mass spectrometry to identify altered lipids in resected brain specimens from FCD patients compared to non-epileptic controls. Based on these results, we propose that a similar approach utilizing unique lipid mass spectra can be used for defining the EZs in FCD. The observed distinct lipid mass spectra of cortical tissues from FCD patients could be used for real-time guidance during surgery as well as for ex vivo examination of resected tissues for diagnostic purposes.

Production and Immunogenicity of a Tag-Free Recombinant Chimera Based on PfMSP-1 and PfMSP-3 Using Alhydrogel and Dipeptide-Based Hydrogels.

A fusion chimeric vaccine comprising multiple protective domains of different blood-stage Plasmodium falciparum antigens is perhaps necessary for widening the protective immune responses and reducing the morbidity caused by the disease. Here we continue to build upon the prior work of developing a recombinant fusion chimera protein, His-tagged PfMSP-Fu24, by producing it as a tag-free recombinant protein. In this study, tag-free recombinant PfMSPFu24 (rFu24) was expressed in Escherichia coli, and the soluble protein was purified using a three-step purification involving ammonium sulphate precipitation followed by 2-step ion exchange chromatography procedures and shown that it was highly immunogenic with the human-compatible adjuvant Alhydrogel. We further investigated two dipeptides, phenylalanine-α, ß-dehydrophenylalanine (FΔF) and Leucine-α, ß-dehydrophenylalanine (LΔF) based hydrogels as effective delivery platforms for rFu24. These dipeptides self-assembled spontaneously to form a highly stable hydrogel under physiological conditions. rFu24 was efficiently entrapped in both the F∆F and L∆F hydrogels, and the three-dimensional (3D) mesh-like structures of the hydrogels remained intact after the entrapment of the antigen. The two hydrogels significantly stimulated rFu24-specific antibody titers, and the sera from the immunized mice showed an invasion inhibitory activity comparable to that of Alhydrogel. Easily synthesized dipeptide hydrogels can be used as an effective antigen delivery platform to induce immune responses.

Transcriptomic profiling of high- and low-spiking regions reveals novel epileptogenic mechanisms in focal cortical dysplasia type II patients.

Focal cortical dysplasia (FCD) is a malformation of the cerebral cortex with poorly-defined epileptogenic zones (EZs), and poor surgical outcome in FCD is associated with inaccurate localization of the EZ. Hence, identifying novel epileptogenic markers to aid in the localization of EZ in patients with FCD is very much needed. High-throughput gene expression studies of FCD samples have the potential to uncover molecular changes underlying the epileptogenic process and identify novel markers for delineating the EZ. For this purpose, we, for the first time performed RNA sequencing of surgically resected paired tissue samples obtained from electrocorticographically graded high (MAX) and low spiking (MIN) regions of FCD type II patients and autopsy controls. We identified significant changes in the MAX samples of the FCD type II patients when compared to non-epileptic controls, but not in the case of MIN samples. We found significant enrichment for myelination, oligodendrocyte development and differentiation, neuronal and axon ensheathment, phospholipid metabolism, cell adhesion and cytoskeleton, semaphorins, and ion channels in the MAX region. Through the integration of both MAX vs non-epileptic control and MAX vs MIN RNA sequencing (RNA Seq) data, PLP1, PLLP, UGT8, KLK6, SOX10, MOG, MAG, MOBP, ANLN, ERMN, SPP1, CLDN11, TNC, GPR37, SLC12A2, ABCA2, ABCA8, ASPA, P2RX7, CERS2, MAP4K4, TF, CTGF, Semaphorins, Opalin, FGFs, CALB2, and TNC were identified as potential key regulators of multiple pathways related to FCD type II pathology. We have identified novel epileptogenic marker elements that may contribute to epileptogenicity in patients with FCD and could be possible markers for the localization of EZ.

Mechanistic Investigations of Growth of Anisotropic Nanostructures in Reverse Micelles.

Tailoring the characteristics of anisotropic nanostructures like size, morphology, aspect ratio, and size dispersity is of extreme importance due to the unique and tunable properties including catalytic, optical, photocatalytic, magnetic, photochemical, electrochemical, photoelectrochemical, and several other physical properties. The reverse microemulsion (RM) method offers a useful soft-template and low-temperature procedure that, by variation of experimental conditions and nature of reagents, has proved to be extremely versatile in synthesis of nanostructures with tailored properties. Although many reports of synthesis of nanostructures by the RM method exist in the literature, most of the research studies carried out still follow the "hit and trial" method where the synthesis conditions, reagents, and other factors are varied and the resulting characteristics of the obtained nanostructures are justified on the basis of existing physical chemistry principles. Mechanistic investigations are scarce to generate a set of empirical rules that would aid in preplanning the RM-based synthesis of nanostructures with desired characteristics as well as make the process viable on an industrial scale. A consolidation of such research data available in the literature is essential for providing future directions in the field. In this perspective, we analyze the literature reports that have investigated the mechanistic aspects of growth of anisotropic nanostructures using the RM method and distil the essence of the present understanding at the nanoscale timescale using techniques like FCS and ultrafast spectroscopy in addition to routine techniques like DLS, fluorescence, TEM, etc.

Redox-Responsive Dipeptide Nanostructures toward Targeted Cancer Therapy.

Materials that exhibit responsiveness toward biological signals are currently subjected to intense research in the field of drug delivery. In our study, we tried to develop cancer-targeted and redox-responsive nanoparticles (NPs) from disulfide-linked oxidized cysteine-phenylalanine (CFO). The NPs were conjugated with folic acid (FA) to specifically target cancer cells, and the presence of disulfide bonds would enabled the disintegration of the particles in the presence of elevated levels of glutathione (GSH) in cancer cells. Anticancer drug doxorubicin (Dox) was successfully loaded inside the disulfide-linked nanoparticles (CFO-Dox-NPs), which further demonstrated stimuli-responsive drug release in the presence of GSH. We have also demonstrated enhanced uptake of FA-derivatized NPs (FA-CFO-NPs) in cancerous cells (C6 glioma and B16F10 melanoma cells) than in normal cells (HEK293T cells) due to the overexpression of FA receptors on the surface of cancer cells. Cytotoxicity studies in C6 cells and B16F10 cells further revealed enhanced efficacy of Dox loaded (FA-CFO-Dox-NPs) as compared to the native drug. The findings of this study clearly demonstrated that the disulfide-linked nanoparticle system may provide a promising selective drug delivery platform in cancer cells.

Short to ultrashort peptide-based hydrogels as a platform for biomedical applications.

Short peptides have attracted significant attention from researchers in the past few years due to their easy design, synthesis and characterization, diverse functionalisation possibilities, low cost, possibility to make a large range of hierarchical nanostructures and most importantly their high biocompatibility and biodegradability. Generally, short peptides are also relatively more stable than their longer variants, non-immunogenic in nature and many of them self-assemble to provide an exciting range of nanostructures, including hydrogels. Thus, the development of short peptide-based hydrogels has become an area of intense investigation. Although these hydrogels have a water content of greater than 90%, they are surprisingly highly stable structures, and thus have been used for various biomedical applications, including cell therapeutics, drug delivery, tissue engineering and regeneration, contact lenses, biosensors, and wound healing, by different researchers. Herein, we review the progress of research in the rapidly expanding field of short to ultrashort peptide-based hydrogels and their possible applications. Special attention is paid to address and review this field with regard to the stability of peptide-based hydrogels, particularly to enzymatic degradation.