Association between impulsivity and depressive symptoms in recently detoxified patients with alcohol dependence.

Background: Depression and impulsivity are etiologically linked to alcohol dependence (AD) and are known to affect course and outcomes. The relationship between impulsivity and depressive symptoms has been investigated only in a few studies of individuals with AD. Aim: This study aimed to explore the association between impulsivity and depressive symptoms in patients with AD. Materials and Methods: Our study was conducted in the inpatient setup of a tertiary care psychiatry institute. The study design is cross-sectional. The Barratt Impulsiveness Scale (BIS-11) and stop signal task (SST) were used to assess levels of global impulsivity and behavioral impulsivity, respectively, among 60 recently detoxified inpatients with AD. The Hamilton Depression Rating Scale (HAM-D) was used to measure depressive symptoms. The results were analyzed to examine the association of depressive symptoms with impulsivity. Pearson's coefficient of correlation or Spearman's rank correlation and linear regression analysis were performed to explore the association between quantitative variables. Results: Patients with higher HAM-D scores were found to have significantly higher score on all three subscales of the BIS-11. The attention impulsivity subscale had the strongest correlations (r = 0.53, P < 0.001). Depressive symptoms were more strongly correlated with cognitive impulsivity (r = 0.54, P< 0.0001) compared with motor impulsivity and were not significantly associated with behavioral impulsivity. Adjusting for other variables, cognitive impulsivity was found to be the strongest predictor of the severity of depressive symptoms. Conclusions: The study showed a strong association between impulsivity and depressive symptoms in individuals with AD. This relationship may apply more to cognitive impulsivity, reflecting the role of impulsive decisions compared with impulsive actions.

Decellularized porcine peripheral nerve based injectable hydrogels as a Schwann cell carrier for injured spinal cord regeneration.

OBJECTIVE: To develop a clinically relevant injectable hydrogel derived from decellularized porcine peripheral nerves and with mechanical properties comparable to native central nervous system (CNS) tissue to be used as a delivery vehicle for Schwann cell transplantation to treat spinal cord injury (SCI). APPROACH: Porcine peripheral nerves (sciatic and peroneal) were decellularized by using a sodium deoxycholate and DNase (SDD) method previously developed by our group. The decellularized nerves were delipidated using dichloromethane and ethanol solvent and then digested using pepsin enzyme to form injectable hydrogel formulations. Genipin was used as a crosslinker to enhance mechanical properties. The injectability, mechanical properties, and gelation kinetics of the hydrogels were further analyzed using rheology. Schwann cells encapsulated within the injectable hydrogel formulations were passed through a 25-gauge needle and cell viability was assessed using live/dead staining. The ability of the hydrogel to maintain Schwann cell viability against an inflammatory milieu was assessed in vitro using inflamed astrocytes co-cultured with Schwann cells. RESULTS: The SDD method effectively removes cells and retains extracellular matrix in decellularized tissues. Using rheological studies, we found that delipidation of decellularized porcine peripheral nerves using dichloromethane and ethanol solvent improves gelation kinetics and mechanical strength of hydrogels. The delipidated and decellularized hydrogels crosslinked using genipin mimicked the mechanical strength of CNS tissue. The hydrogels were found to have shear thinning properties desirable for injectable formulations and they also maintained higher Schwann cell viability during injection compared to saline controls. Using in vitro co-culture experiments, we found that the genipin-crosslinked hydrogels also protected Schwann cells from astrocyte-mediated inflammation. SIGNIFICANCE: Injectable hydrogels developed using delipidated and decellularized porcine peripheral nerves are a potential clinically relevant solution to deliver Schwann cells, and possibly other therapeutic cells, at the SCI site by maintaining higher cellular viability and increasing therapeutic efficacy for SCI treatment.

BM-MSC-Loaded Graphene-Collagen Cryogels Ameliorate Neuroinflammation in a Rat Spinal Cord Injury Model.

A major obstacle to axonal regeneration following spinal cord injury (SCI) is neuroinflammation mediated by astrocytes and microglial cells. We previously demonstrated that graphene-based collagen hydrogels alone can decrease neuroinflammation in SCI. Their regenerative potential, however, is poorly understood and incomplete. Furthermore, stem cells have demonstrated both neuroprotective and regenerative properties in spinal cord regeneration, although there are constraints connected with the application of stem cell-based therapy. In this study, we have analyzed the regeneration capability of human bone marrow mesenchymal stem cell (BM-MSC)-loaded graphene-cross-linked collagen cryogels (Gr-Col) in a thoracic (T10-T11) hemisection model of SCI. Our study found that BM-MSC-loaded Gr-Col improves axonal regeneration, reduces neuroinflammation by decreasing astrocyte reactivity, and promotes M2 macrophage polarization. BM-MSC-loaded-Gr-Col demonstrated enhanced regenerative potential compared to Gr-Col and the injury group control. Next-generation sequencing (NGS) analysis revealed that BM-MSC-loaded-Gr-Col modulates the JAK2-STAT3 pathway, thus decreasing the reactive and scar-forming astrocyte phenotype. The decrease in neuroinflammation in the BM-MSC-loaded-Gr-Col group is attributed to the modulation of Notch/Rock and STAT5a/b and STAT6 signaling. Overall, Gene Set Enrichment Analysis suggests the promising role of BM-MSC-loaded-Gr-Col in promoting axonal regeneration after SCI by modulating molecular pathways such as the PI3/Akt pathway, focal adhesion kinase, and various inflammatory pathways.

Graphene-collagen cryogel controls neuroinflammation and fosters accelerated axonal regeneration in spinal cord injury.

Spinal cord injury (SCI) is a devastating condition resulting in loss of motor function. The pathology of SCI is multifaceted and involves a cascade of events, including neuroinflammation and neuronal degeneration at the epicenter, limiting repair process. We developed a supermacroporous, mechanically elastic, electro-conductive, graphene crosslinked collagen (Gr-Col) cryogels for the regeneration of the spinal cord post-injury. The effects of graphene in controlling astrocytes reactivity and microglia polarization are evaluated in spinal cord slice organotypic culture and rat spinal cord lateral hemisection model of SCI. In our work, the application of external electric stimulus results in the enhanced expression of neuronal markers in an organotypic culture. The implantation of Gr-Col cryogels in rat thoracic T9-T11 hemisection model demonstrates an improved functional recovery within 14 days post-injury (DPI), promoted myelination, and decreases the lesion volume at the injury site. Decrease in the expression of STAT3 in the implanted Gr-Col cryogels may be responsible for the decrease in astrocytes reactivity. Microglia cells within the implanted cryogels shows higher anti-inflammatory phenotype (M2) than inflammatory (M1) phenotype. The higher expression of mature axonal markers like ß-tubulin III, GAP43, doublecortin, and neurofilament 200 in the implanted Gr-Col cryogel confirms the axonal regeneration after 28 DPI. Gr-Col cryogels also modulate the production of ECM matrix, favouring the axonal regeneration. This study shows that Gr-Col cryogels decreases neuroinflammation and accelerate axonal regeneration.

Neonatal acute kidney injury risk stratification score: STARZ study.

BACKGROUND: Neonates admitted in the neonatal intensive care unit are vulnerable to acute kidney injury leading to worse outcomes. It is important to identify "at-risk" neonates for early preventive measures. METHODS: The study was a multicenter, national, prospective cohort study done in 11 centers in India. A multivariable logistic regression technique with step-wise backward elimination method was used, and a "Risk Prediction Scoring" was devised [the STARZ score]. RESULTS: The neonates with admission in the NICU within <25.5 h of birth, requirement of positive pressure ventilation in the delivery room, <28 weeks gestational age, sepsis, significant cardiac disease, urine output <1.32 ml/kg/h or serum creatinine ≥0.98 mg/dl during the first 12 h post admission, use of nephrotoxic drugs, use of furosemide, or use of inotrope had a significantly higher risk of AKI at 7 days post admission in the multivariate logistic regression model. This scoring model had a sensitivity of 92.8%, specificity of 87.4% positive predictive value of 80.5%, negative predictive value of 95.6%, and accuracy of 89.4%. CONCLUSIONS: The STARZ neonatal score serves to rapidly and quantitatively determine the risk of AKI in neonates admitted to the neonatal intensive care unit. IMPACT: The STARZ neonatal score serves to rapidly and quantitatively determine the risk of AKI in neonates admitted to the neonatal intensive care unit. These neonates with a higher risk stratification score need intense monitoring and daily kidney function assessment. With this intensification of research in the field of AKI risk stratification prediction, there is hope that we will be able to decrease morbidity and mortality associated with AKI in this population.

X-ray tomography analysis reveals the influence of graphene on porous morphology of collagen cryogels.

X-ray micro-tomography based analysis of porous hydrogel has gained a wide attention recently. It provides an advantage in three-dimensional analysis of pore morphometric and interconnection within the hydrogel network. We have fabricated highly elastic graphene crosslinked collagen hydrogel using cryogelation technique. The influence of graphene as a nano-crosslinker on the overall porosity and inter-connections between the pores in collagen cryogels was determined using X-ray micro-tomography. We have evaluated the effect of different concentration of amino-functionalized graphene nano-crosslinker on collagen cryogels porosity, pore volume, interconnectivity density, fractal dimensions and pore wall thickness. This study, reveals that the use of graphene as a nano-crosslinker have improved micro-architecture as compare to collagen cryogels in the absence of graphene for tissue engineering applications.

Design, synthesis and in-vitro evaluation of fluorinated triazoles as multi-target directed ligands for Alzheimer disease.

Alzheimer disease is multi-factorial and inflammation plays a major role in the disease progression and severity. Metals and reactive oxygen species (ROS) are the key mediators for inflammatory conditions associated with Alzheimer's. Along multi-factorial nature, major challenge for developing new drug is the ability of the molecule to cross blood brain barrier (BBB). We have designed and synthesized multi-target directed hexafluorocarbinol containing triazoles to inhibit Amyloid ß aggregation and simultaneously chelate the excess metals present in the extracellular space and scavenge the ROS thus reduce the inflammatory condition. From the screened compound library, compound 1c found to be potent and safe. It has demonstrated inhibition of Amyloid ß aggregation (IC50 of 4.6 µM) through selective binding with Amyloid ß at the nucleation site (evidenced from the molecular docking). It also chelate metals (Cu+2, Zn+2 and Fe+3) and scavenges ROS significantly. Due to the presence of hexafluorocarbinol moiety in the molecule it may assist to permeate BBB and improve the pharmacokinetic properties. The in-vitro results of compound 1c indicate the promiscuity for the development of hexafluorocarbinol containing triazoles amide scaffold as multi-target directed therapy against Alzheimer disease.

Highly elastic, electroconductive, immunomodulatory graphene crosslinked collagen cryogel for spinal cord regeneration.

Novel amino-functionalized graphene crosslinked collagen based nerve conduit having appropriate electric (3.8 ± 0.2 mSiemens/cm) and mechanical cues (having young modulus value of 100-347 kPa) for stem cell transplantation and neural tissue regeneration was fabricated using cryogelation. The developed conduit has shown sufficiently high porosity with interconnectivity between the pores. Raman spectroscopy analysis revealed the increase in orderliness and crosslinking of collagen molecules in the developed cryogel due to the incorporation of amino-functionalized graphene. BM-MSCs grown on graphene collagen cryogels have shown enhanced expression of CD90 and CD73 gene upon electric stimulation (100 mV/mm) contributing towards maintaining their stemness. Furthermore, an increased secretion of ATP from BM-MSCs grown on graphene collagen cryogel was also observed upon electric stimulation that may help in regeneration of neurons and immuno-modulation. Neuronal differentiation of BM-MSCs on graphene collagen cryogel in the presence of electric stimulus showed an enhanced expression of MAP-2 kinase and ß-tubulin III. Immunohistochemistry studies have also demonstrated the improved neuronal differentiation of BM-MSCs. BM-MSCs grown on electro-conductive collagen cryogels under inflammatory microenvironment in vitro showed high indoleamine 2,3 dioxygenase activity. Moreover, macrophages cells grown on graphene collagen cryogels have shown high CD206 (M2 polarization marker) and CD163 (M2 polarization marker) and low CD86 (M1 polarization marker) gene expression demonstrating M2 polarization of macrophages, which may aid in tissue repair. In an organotypic culture, the developed cryogel conduit has supported cellular growth and migration from adult rat spinal cord. Thus, this novel electro-conductive graphene collagen cryogels have potential for suppressing the neuro-inflammation and promoting the neuronal cellular migration and proliferation, which is a major barrier during the spinal cord regeneration.

Hyaluronic acid containing scaffolds ameliorate stem cell function for tissue repair and regeneration.

Recent evidence based studies have proposed hyaluronic acid (HA) as an emerging biopolymer for various tissue engineering application. Meanwhile, stem cells (SCs) have also gained immense popularity for their tissue regenerative capacity. Thus, combining HA and stem cells for tissue engineering application have shown to foster tissue repair and regeneration process. HA possesses the ability to interact with SCs via cellular surface receptors along with the capacity to elicit the process of differentiation. The influence of HA on stem cells has been widely investigated in cartilage and bone repair but their properties of reducing inflammation has also been explored in various other tissue repair processes. In this review, we have provided an insight to the effect of crosslinked and non-crosslinked HA on various stem cells. Further, HA based scaffolds combined with stem cells have shown to have a synergistic effect in the regeneration capacity. Also, various chemically modified HA and biomolecules conjugated HA as a suitable carrier or matrix for stem cells delivery and the effect of HA in fine tuning the stem cells function is discussed.

Biomolecule-Conjugated Macroporous Hydrogels for Biomedical Applications.

Biomolecule-conjugated macroporous hydrogels have been investigated in the fields of bioseparation, biocatalysts, bioreactors, cell therapy, tissue regeneration, and environmental applications. This review focuses on different types of biological molecules that have been conjugated on macroporous hydrogels. A variety of techniques are available for the fabrication of macroporous hydrogels and attachment of biomolecules. Natural polymers, ECM components, growth factors, peptides, and proteins have been widely used for the functionalization of macroporous hydrogels for various biomedical applications. The major areas benefited by the incorporation of these biomolecules are separation of cells and biomolecules (e.g., antibodies), tissue repair and regeneration (e.g., peptides and ECM molecules), biocatalysts (e.g., enzymes), and control of environmental pollution. Additionally, functionalization of macroporous hydrogels with chemical drugs has demonstrated their controlled drug release capabilities. Moreover, clinically available biofunctionalized macroporous polymeric products have been briefly discussed.

Ultrafiltration membrane for effective removal of chromium ions from potable water.

The objective of the present work was to investigate the efficacy of indigenously developed polyacrylonitrile (PAN) based ultrafiltration (UF) membrane for chromium ions removal from potable water. The hydrolyzed PAN membranes effectively rejected chromium anions in the feed ranging from 250 ppb to 400 ppm and a rejection of ≥90% was achieved for pH ≥ 7 at low chromate concentration (≤25 ppm) in feed. The rejection mechanism of chromium ions was strongly dependent on Donnan exclusion principle, while size exclusion principle for UF did not play a major role on ions rejection. Feed pH played a vital role in changing porosity of membrane, which influenced the retention behavior of chromate ions. Cross-flow velocity, pressure did not play significant role for ions rejection at low feed concentration. However, at higher feed concentration (≥400 ppm), concentration polarization became important and it reduced the chromate rejection to 32% at low cross flow and high pressure. Donnan steric-partitioning pore and dielectric exclusion model (DSPM-DE) was applied to evaluate the chromate ions transport through PAN UF membrane as a function of flux by using optimized model parameters and the simulated data matched well with experimental results.

Novel expression system for Corynebacterium acetoacidophilum and Escherichia coli based on the T7 RNA polymerase-dependent promoter.

The industrially important species of corynebacteria viz. Corynebacterium acetoacidophilum appear to be alternative hosts for recombinant protein production; despite many efforts, a strong promoter-based system in corynebacteria has not been established so far. Described here is a T7 promoter-based expression system which was functional in both gram-positive C. acetoacidophilum and gram-negative Escherichia coli in an external inducer independent manner. This is the very first report of a T7 expression system for Corynebacterium sp. Also, it is a useful addition in the existing T7 expression systems of E. coli.

Modeling of the separation of inhibitory components from pretreated rice straw hydrolysate by nanofiltration membranes.

The main objective of this work was to remove inhibitors and concentrate sugars in hydrolysates obtained from dilute acid-treated rice straw. The Donnan steric pore flow model (DSPM) was applied for membrane characterization and it captured the membrane transport adequately. The polyamide and polyethylene sulfate nanofiltration membranes of 150 Da molecular weight cut-off showed a separation factor of 3 for acetic acid over glucose and xylose and 7 over cellobiose for a simulated mixture at the optimum pH of 3. A separation factor of 3 was also found for the inhibitors hydroxymethyl furfural, ferulic and vanilic acids over sugars. The concentration of rice straw acid hydrolysate by a volume concentration ratio of 4 increased the concentrations of xylose, glucose, arabinose, cellobiose and inhibitor by 100%, 104%, 93%, 151% and 3%, respectively which indicates the membrane can be used for separating the inhibitors from acid-pretreated rice straw hydrolysate while simultaneously concentrating sugars.

Phase synchronization of the ongoing EEG and auditory EP generation.

OBJECTIVE: We investigated the role of phase synchronization of the spontaneous electroencephalogram (EEG) in auditory evoked potential (EP) generation in a sample of healthy individuals. METHODS: Auditory responses were obtained from 20 healthy subjects following a double stimulus paradigm, using two identical tone bursts (S1 and S2) separated by 0.5s. Single-trial auditory evoked potentials were decomposed into sinusoidal, exponentially decaying/increasing components using the piecewise Prony method (PPM). Pre- and post-stimulus phase histograms were compared to determine the degree of phase synchronization produced by auditory stimulation. RESULTS: Analysis of single responses revealed that the S1 stimuli produced phase synchronization in the 2-8Hz frequency range, with little or no concomitant amplitude increase. A significantly reduced phase effect was seen in response to S2 stimuli. CONCLUSIONS: Stimulus-induced phase synchronization of the ongoing EEG is a major mechanism for the generation of auditory EP components with a latency in the 50-250ms range. SIGNIFICANCE: The fact that the EP components accessed here are generated through phase synchronization implies that the ensemble-averaged EP will not resemble the single trial response, and it would certainly be misleading to consider the single trial response as an amplitude-scaled version of the ensemble average.

Effect of oxygen transfer on glycerol biosynthesis by an osmophilic yeast Candida magnoliae I(2)B.

The influence of oxygen on glycerol production by an osmophilic yeast, Candida magnoliae I(2)B, was studied in a bioreactor. Oxygen transfer rates (OTRs) and volumetric oxygen transfer coefficients (k(L)a) were determined at different aeration and agitation rates. Cell growth as well as glycerol production was strongly affected by oxygen supply. Improvement in OTRs resulted in increased cell growth and glycerol yield. However, at high OTRs, there was a reduction in glucose uptake rate, indicating Pasteur Effect, and glycerol accumulation was also reduced at k(L)a of 253 h(-1). The availability of oxygen per unit of cell mass was found to be the most important factor that controlled cell growth, glucose uptake, and glycerol yield. The overall productivity and yield of glycerol could be related with k(L)a. The biosynthesis of glycerol was found to both growth- and non-growth-associated, although glycerol was mainly produced in post-exponential phase.