Recent data suggest that HLA epitope matching is beneficial for the prevention of de novo donor specific antibody (DSA) formation after transplantation. In this review, different approaches to predict the immunogenicity of an HLA mismatch will be discussed. The parameters used in these models are often called epitopes but the actual antibody epitope is far more complex. Exact knowledge of the antibody epitope is crucial if epitope matching is also used as a tool to select compatible donors for (highly) sensitized patients. Evidence is provided that it is not always possible to give an exact definition of an antibody epitope. We conclude that HLA "epitope" matching is superior over HLA antigen matching with respect to the prevention of de novo DSA formation and will enhance the prediction of acceptable HLA mismatches for sensitized patients. However, epitope matching at our current level of knowledge will not solve all histocompatibility problems as unexpected antibody reactivity still may occur.

In budding yeast, a collar of septin filaments at the neck between a mother cell and its bud marks the incipient site for cell division and serves as a scaffold that recruits proteins required for proper spatial and temporal execution of cytokinesis. A set of interacting proteins that localize at or near the bud neck, including Aim44/Gps1, Nba1 and Nis1, also has been implicated in preventing Cdc42-dependent bud site re-establishment at the division site. We found that, at their endogenous level, Aim44 and Nis1 robustly localize sequentially at the septin collar. Strikingly, however, when overproduced, both proteins shift their subcellular distribution predominantly to the nucleus. Aim44 localizes with the inner nuclear envelope, as well as at the plasma membrane, whereas Nis1 accumulates within the nucleus, indicating that these proteins normally undergo nucleocytoplasmic shuttling. Of the 14 yeast karyopherins, Kap123/Yrb4 is the primary importin for Aim44, whereas several importins mediate Nis1 nuclear entry. Conversely, Kap124/Xpo1/Crm1 is the primary exportin for Nis1, whereas both Xpo1 and Cse1/Kap109 likely contribute to Aim44 nuclear export. Even when endogenously expressed, Nis1 accumulates in the nucleus when Nba1 is absent. When either Aim44 or Nis1 are overexpressed, Nba1 is displaced from the bud neck, further consistent with the mutual interactions of these proteins. Collectively, our results indicate that a previously unappreciated level at which localization of septin-associated proteins is controlled is via regulation of their nucleocytoplasmic shuttling, which places constraints on their availability for complex formation with other partners at the bud neck.

Intraductal papillary mucinous neoplasms (IPMNs) are regarded as precursors of pancreatic ductal adenocarcinomas (PDAs), but little is known about the mechanism of progression. This makes it challenging to assess cancer risk in patients with IPMNs. We investigated associations of IPMNs with concurrent PDAs by genetic and histologic analyses.

miR-132 and miR-212 are structurally-related microRNAs that are expressed from the same non-coding transcript. Accumulating evidence has shown that the dysregulation of these microRNAs contributes to aberrant neuronal plasticity and gene expression in the mammalian brain. Consistent with this, altered expression of miR-132 is associated with a number of affect-related psychiatric disorders. Here, we tested the functional contribution of the miR-132/212 locus to the development of stress-related and anxiety-like behaviors. Initially, we tested whether expression from the miR-132/212 locus is altered by stress-inducing paradigms. Using a 5-h acute-stress model, we show that both miR-132 and miR-212 are increased more than two-fold in the WT murine hippocampus and amygdala, whereas after a 15 day chronic-stress paradigm, expression of both miR-132 and miR-212 are upregulated more than two-fold within the amygdala but not in the hippocampus. Next, we used a tetracycline-inducible miR-132 overexpression mouse model and a miR-132/212 conditional knockout (cKO) mouse model to examine whether dysregulation of miR-132/212 expression alters basal anxiety-like behaviors. Interestingly, in both the miR-132 overexpression and cKO lines, significant increases in anxiety-like behaviors were detected. Importantly, suppression of transgenic miR-132 expression (via doxycycline administration) mitigated the anxiety-related behaviors. Further, expression of Sirt1 and Pten-two miR-132 target genes that have been implicated in the regulation of anxiety-were differentially regulated in the hippocampus and amygdala of miR-132/212 conditional knockout and miR-132 transgenic mice. Collectively, these data raise the prospect that miR-132 and miR-212 may play a key role in the modulation of stress responsivity and anxiety.

Diabetes mellitus type 1 and type 2 have become a global epidemic with dramatically increasing incidences. Poorly controlled diabetes is associated with severe life-threatening complications. Beside traditional treatment with insulin and oral anti-diabetic drugs, clinicians try to improve patient's care by cell therapies using embryonic stem cells (ESC), induced pluripotent stem cells (iPSC) and adult mesenchymal stem cells (MSC). ESC display a virtually unlimited plasticity, including the differentiation into insulin producing β-cells, but they raise ethical concerns and bear, like iPSC, the risk of tumours. IPSC may further inherit somatic mutations and remaining somatic transcriptional memory upon incomplete re-programming, but allow the generation of patient/disease-specific cell lines. MSC avoid such issues but have not been successfully differentiated into β-cells. Instead, MSC and their pericyte phenotypes outside the bone marrow have been recognized to secrete numerous immunomodulatory and tissue regenerative factors. On this account, the term 'medicinal signaling cells' has been proposed to define the new conception of a 'drug store' for injured tissues and to stay with the MSC nomenclature. This review presents the biological background and the resulting clinical potential and limitations of ESC, iPSC and MSC, and summarizes the current status quo of cell therapeutic concepts and trials.

Intracranial photometry through chronically implanted optical fibers is a widely adopted technique for measuring signals from fluorescent probes in deep-brain structures. The recent proliferation of bright, photo-stable, and specific genetically encoded fluorescent reporters for calcium and for other neuromodulators has greatly increased the utility and popularity of this technique.

Donation after circulatory death (DCD) liver transplantation is known for potentially worse outcomes because of higher rates of graft non-function or irreversible cholangiopathy. The impact of machine liver perfusion techniques on these complications remains elusive. We aimed to provide data on 5-year outcomes in patients receiving DCD liver transplants, after donor organs had been treated by hypothermic oxygenated perfusion (HOPE).

Polysaccharides from Laminaria japonica (LJPs) are reported to have various functional properties, but the effects and mechanisms of LJPs on obesity and its related diseases are unclear. This study demonstrated that LJPs prevented diet-induced obesity in a mice model, and improved obesity-related parameters, e.g. fat accumulation in the liver and adipose tissues, body composition, lipids profile, and the morphology of the intestine. Such effects were associated with the modulation of the gut microbiota, involving some members of the Bacteroidetes phylum. Changes in the gut microbiota could improve nutrient utilization, increase microbial metabolites production, and thus regulate lipids metabolism in the body. In short, it sought to indicate that L. japonica can be developed as food supplement for the improvement of metabolic syndrome and the human gut health.

Electrospun nanofibrous mats based on biopolymers have been widely investigated for tissue engineering in recent years, primarily due to remarkable morphological similarity to the natural extracellular matrix (ECM). In this research, electrospun PVA/Chitosan/Starch nanofibrous mats were fabricated using electrospinning method for wound dressing application. The prepared nanofibrous mats were then cross-linked to enhanced the water resistance and also optimize the biodegradation rate followed by characterization and evaluation of their properties as wound dressings. The morphological studies performed by SEM and AFM showed that uniform bead-free electrospun nanofibrous mats were formed. The structural properties of the fabricated mats were characterized by FTIR. The proper porosity and balanced water absorption and water vapor transmission rate (WVTR) of obtained dressings, demonstrate their ability in providing suitable moist environment for wound, result in the appropriate wound breathing and simultaneously efficient handling of wound exudates. Suitable mechanical properties of nanofibrous dressing in both dry and wet states confirm the capability of fabricated wound dressing to protect wound area against the external forces during the healing process. Antibacterial test revealed excellent antibacterial activity of nanofibrous mats against both gram negative and gram positive bacteria. Furthermore, the in vitro cytotoxicity evaluated by MTT assay, proved appropriate cytocompatibility and cell viability of the developed nanofibrous mats which were also verified with in vitro wound healing analysis performed by scratch assay, confirming the remarkable potential of the investigated nanofibrous mats for wound dressing application.

Less attention has been focused on the industrial applications of levan-type fructan than that of inulin. Levan-type fructan is a unique homopolysaccharide consisting of fructose residues with a β-(2, 6) linkage that possesses unique physiochemical properties such as low intrinsic viscosity. In this study, the recombinant levansucrase from Erwinia amylovora was used to efficiently produce levan from sucrose, and under optimised conditions, 195 g/L levan was produced from 500 g/L sucrose, with the highest conversion rate of 59%. The physicochemical properties of E. amylovora levan, such as surface morphology, thermal behaviour, rheology behaviour and texture analysis, were evaluated and compared with those of commercial gels, including xanthan, guar, carrageenan and Arabic gums. The produced E. amylovora levan showed a series of acceptable physicochemical properties, indicating a potential application for levan as a novel water-soluble micro gel. The conclusions of this study support the exploration of the use of more hydrogels in the food, medicinal and cosmetic industries.

The role of sleep in brain physiology is poorly understood. Recently rodent studies have shown that the glymphatic system clears waste products from brain more efficiently during sleep compared to wakefulness due to the expansion of the interstitial fluid space facilitating entry of cerebrospinal fluid (CSF) into the brain. Here, we studied water diffusivity in the brain during sleep and awake conditions, hypothesizing that an increase in water diffusivity during sleep would occur concomitantly with an expansion of CSF volume - an effect that we predicted based on preclinical findings would be most prominent in cerebellum. We used MRI to measure slow and fast components of the apparent diffusion coefficient (ADC) of water in the brain in 50 healthy participants, in 30 of whom we compared awake versus sleep conditions and in 20 of whom we compared rested-wakefulness versus wakefulness following one night of sleep-deprivation. Sleep compared to wakefulness was associated with increases in slow-ADC in cerebellum and left temporal pole and with decreases in fast-ADC in thalamus, insula, parahippocampus and striatal regions, and the density of sleep arousals was inversely associated with ADC changes. The CSF volume was also increased during sleep and was associated with sleep-induced changes in ADCs in cerebellum. There were no differences in ADCs with wakefulness following sleep deprivation compared to rested-wakefulness. Although we hypothesized increases in ADC with sleep, our findings uncovered both increases in slow ADC (mostly in cerebellum) as well as decreases in fast ADC, which could reflect the distinct biological significance of fast- and slow-ADC values in relation to sleep. While preliminary, our findings suggest a more complex sleep-related glymphatic function in the human brain compared to rodents. On the other hand, our findings of sleep-induced changes in CSF volume provide preliminary evidence that is consistent with a glymphatic transport process in the human brain.

The lateral geniculate nucleus (LGN) is an essential nucleus of the visual pathway, occupying a small volume (60-160 mm3) among the other thalamic nuclei. The reported LGN volumes vary greatly across studies due to technical limitations and due to methodological differences of volume assessment. Yet, structural and anatomical alterations in ophthalmologic and neurodegenerative pathologies can only be revealed by a precise and reliable LGN representation. To improve LGN volume assessment, we first implemented a reference acquisition for LGN volume determination with optimized Contrast to Noise Ratio (CNR) and high spatial resolution. Next, we compared CNR efficiency and rating reliability of 3D Magnetization Prepared Rapid Gradient Echo (MPRAGE) images using white matter nulled (WMn) and grey matter nulled (GMn) sequences and its subtraction (WMn-GMn) relative to the clinical standard Proton Density Turbo Spin Echo (PD 2D TSE) and the reference acquisition. We hypothesized that 3D MPRAGE should provide a higher CNR and volume determination accuracy than the currently used 2D sequences.

Endogenous retroviruses (ERVs) comprise 10% of the genome, with many of these transcriptionally silenced post early embryogenesis. Several stimuli, including exogenous virus infection and cellular transformation can reactivate ERV expression via a poorly understood mechanism. We identified Interferon Regulatory Factor 1 (IRF-1), a tumor suppressor and an antiviral host factor, as a suppressor of ERV expression. IRF-1 decreased expression of a specific mouse ERV in vitro and in vivo. IRF-3, but not IRF-7, also decreased expression of distinct ERV families, suggesting that suppression of ERVs is a relevant biological function of the IRF family. Given the emerging appreciation of the physiological relevance of ERV expression in cancer, IRF-1-mediated suppression of specific ERVs may contribute to the overall tumor suppressor activity of this host factor.

Gingival recession and alveolar bone loss are common manifestations of periodontitis. Periodontal regeneration is the ideal strategy for rehabilitating periodontal tissue defects and preventing tooth loss. The present study examined whether localized, topical application of gingival overgrowth-inducing drugs, phenytoin, nifedipine or cyclosporine, induces periodontal regeneration.

Intermediate-length ATXN2 CAG repeats are a risk factor for amyotrophic lateral sclerosis (ALS). Here we report on a female patient with heterozygous repeat expansion mutation in the CACNA1A gene presenting with a pure ALS syndrome while her father, who also carries that CACNA1A mutation, suffers from a classical spinocerebellar ataxia type 6. Hypothesizing that CACNA1A CAG repeat expansions could be a monogenic cause for familial ALS (fALS), we analyzed the CAG repeat lengths in CACNA1A in a large cohort of genetically unexplained patients with fALS. Our results indicate that CAG repeat expansion mutations in CACNA1A are not a frequent monogenic cause of fALS but could phenotypically present as ALS in rare instances.

Bacterial cellulose (BC) is gaining considerable attention due to its unique physicochemical and mechanical properties. In this study, BC production by Gluconacetobacter xylinus PTCC 1734 in sugar beet molasses, cheese whey and standard Hestrin-Schramm (HS) media was evaluated. The synthesized BC was hydrolyzed by sulfuric acid to prepare bacterial cellulose nanocrystals (BCNC). The results showed that treated sugar beet molasses led to the highest BC concentration and productivity, followed by treated cheese whey. Structural analysis of BC and BCNC was carried out by Fourier Transform Infrared (FTIR) spectroscopy. The crystallinity index of the BCNC determined by X-ray diffraction (XRD) was higher than BC. The morphological analysis carried out by FE-SEM showed that microfibrils diameter decreases with acid treatment. TEM images confirmed the formation of rod like cellulose nanocrystals having an average diameter and length of 25 ± 5 and 306 ± 112 nm, respectively. In conclusion, food industrial byproducts can be used as cost-effective culture media to produce BC for large-scale industrial production and isolated cellulose nanocrystals are useful in the fabrication of bio-nanocomposite films for food packaging applications.

We aimed to test the adsorption of the methylene blue (MB) on HSEPCGUM as a dye and also to test the obtained ternary biocomposite substance (HSEPCGUM-MB) on wound healing. Hollow silica spheres (HSS) are used in the pharmaceutical and biochemical field, because of low toxic, highly biocompatible and mechanically stable by large surface areas. HSS was obtained by mechanochemistry method. The obtained HSS was treated with epichlorohydrin to carry out an epoxidation process (HSEPC). Then, HSEPC was functionalized by treatment with gum arabic (HSEPCGUM). MB was adsorbed onto HSEPCGUM and the adsorption maximum capacity of HSEPCGUM (Xmax) was obtained 333 mg g-1. For in vitro studies, according to the cytotoxicity test results, ternary biocomposite substance (HSEPCGUM-MB) was studied at non-cytotoxic concentrations 10, 50 and 100 μg/ml and wound closure was found as 55% (100 μg/ml) as compared to control.

Thrombolytic agents are routinely used to dissolve blood clot by activating fibrinolytic system. Among different thrombolytic agents available, staphylokinase (SAK) is gaining much attention because of their fibrin specificity and reduced inhibition by α2 antiplasmin. Though SAK had exhibited less circulatory half life, they are equipotent to tissue plasminogen activator and streptokinase and had shown more potency for clot dissolution during retracted thrombi. In this study, SAK was lipid modified at the N-terminal by a protein engineering approach to enhance its stability and activity. Native SAK as well as the gene encoding SAK with lipobox was cloned into E. coli GJ1158 using pRSET-B expression vector for higher expression. The lipid modification of SAK was confirmed by a mobility shift of 1.3 kDa against the 15.5 kDa of native SAK using tricine SDS-PAGE. Lipid modification of SAK was confirmed by LC MS/MS. The secondary structure analysis was carried out using circular dichroism and deconvoluted fourier transform infrared spectroscopy. LMSAK was found to have a slightly higher denaturation temperature compared to SAK. The improved stablility and activity of lipid modified SAK was studied by heated plasma agar plate assay and mouse tail bleeding test.

Cognitive control is proposed to rely on a rostral-to-caudal hierarchy of neural processing within the prefrontal cortex (PFC), with more rostral parts exerting control over more caudal parts. Anatomical and functional data suggest that this hierarchical organization of the PFC may be separated into a ventral and a dorsal component. Furthermore, recent studies indicate that the apex of the hierarchy resides within the mid-lateral rather the rostral PFC. However, investigating the hierarchical aspect of rostro-to-caudal processing requires quantification of the directed interactions between PFC regions. Using functional near-infrared spectroscopy (fNIRS) in a sample of healthy young adults we analyzed directed interactions between rostral and caudal PFC during passive watching of nature documentaries. Directed coherence (DC) as a measure of directed interaction was computed pairwise between 38 channels evenly distributed over the lateral prefrontal convexity. Results revealed an overall predominance of rostral-to-caudal directed interactions in the PFC that further dissociated along a ventro-dorsal axis: Dorsal regions exerted stronger rostro-caudally directed interactions on dorsal than on ventral regions and vice versa. Interactions between ventral and dorsal PFC were stronger from ventral to dorsal areas than vice versa. Results further support the notion that the mid-dorsolateral PFC constitutes the apex of the prefrontal hierarchy. Taken together these data provide novel evidence for parallel dorsal and ventral streams within the rostro-caudal hierarchical organization of the PFC. FNIRS-based analyses of directed interactions put forward a new perspective on the functional architecture of the prefrontal hierarchy and complement previous insights from functional magnetic resonance imaging.

Many gene variants may impair our health and cognitive abilities at old age, but some of them paradoxically improve the same or similar functions at much younger age (antagonistic pleiotropy hypothesis). Such a diametric pattern may also hold true for the ancestral Apolipoprotein E (APOE) ε4 allele, which increases the risk for Alzheimer's disease and cognitive decline in old age, but may benefit (pre)frontal (executive) functions in young carriers. We therefore investigated potential cognitive benefits of the risk allele on cognitive control capacities and top-down control allocation ("metacontrol") in n = 190 healthy young adults. On a behavioral level, we found young APOE ε4 carriers to better adapt to different degrees of cognitive control requirements, with superior performance in case of high control demands. On a neurophysiological level, these group differences were reflected by modulations of the N450 component, which were rooted in activation differences of the superior frontal gyrus (SFG, BA8). Taken together, our results suggest that young ε4 carriers are more efficient than non-carriers at allocating cognitive control resources based on the actual task requirements (i.e. metacontrol), as they seem to experience less conflict/exert less effort and recruit fewer additional prefrontal areas when task set complexity increases. We further found that ε2 carriers processed implicit spatial stimulus features to a stronger degree than ε3 and ε4 carriers, but failed to benefit from this, as the additional information likely increased response selection conflicts. This finding should however be treated with ample caution as the group of ε2 carriers was comparatively small.