Mirror-image ligand discovery enabled by single-shot fast-flow synthesis of D-proteins.

Widespread adoption of mirror-image biological systems presents difficulties in accessing the requisite D-protein substrates. In particular, mirror-image phage display has the potential for high-throughput generation of biologically stable macrocyclic D-peptide binders with potentially unique recognition modes but is hindered by the individualized optimization required for D-protein chemical synthesis. We demonstrate a general mirror-image phage display pipeline that utilizes automated flow peptide synthesis to prepare D-proteins in a single run. With this approach, we prepare and characterize 12 D-proteins - almost one third of all reported D-proteins to date. With access to mirror-image protein targets, we describe the successful discovery of six macrocyclic D-peptide binders: three to the oncoprotein MDM2, and three to the E3 ubiquitin ligase CHIP. Reliable production of mirror-image proteins can unlock the full potential of D-peptide drug discovery and streamline the study of mirror-image biology more broadly.

Diazaborine-Mediated Bicyclization of Native Peptides with Inducible Reversibility.

Multicyclic peptides are appealing candidates for peptide-based drug discovery. While various methods are developed for peptide cyclization, few allow multicyclization of native peptides. Herein we report a novel cross-linker DCA-RMR1, which elicits facile bicyclization of native peptides via N-terminus Cys-Cys cross-linking. The bicyclization is fast, affords quantitative conversion, and tolerates various side chain functionalities. Importantly, the resulting diazaborine linkage, while stable at a neutral pH, can readily reverse upon mild acidification to give pH-responsive peptides.

Optimization of Phage-Antibiotic Combinations against Staphylococcus aureus Biofilms.

Phage therapy has gained attention due to the spread of antibiotic-resistant bacteria and narrow pipeline of novel antibiotics. Phage cocktails are hypothesized to slow the overall development of resistance by challenging the bacteria with more than one phage. Here, we have used a combination of plate-, planktonic-, and biofilm-based screening assays to try to identify phage-antibiotic combinations that will eradicate preformed biofilms of Staphylococcus aureus strains that are otherwise difficult to kill. We have focused on methicillin-resistant S aureus (MRSA) strains and their daptomycin-nonsusceptible vancomycin-intermediate (DNS-VISA) derivatives to understand whether the phage-antibiotic interactions are altered by the changes associated with evolution from MRSA to DNS-VISA (which is known to occur in patients receiving antibiotic therapy). We evaluated the host range and cross-resistance patterns of five obligately lytic S. aureus myophages to select a three-phage cocktail. We screened these phages for their activity against 24-h bead biofilms and found that biofilms of two strains, D712 (DNS-VISA) and 8014 (MRSA), were the most resistant to killing by single phages. Specifically, even initial phage concentrations of 107 PFU per well could not prevent visible regrowth of bacteria from the treated biofilms. However, when we treated biofilms of the same two strains with phage-antibiotic combinations, we prevented bacterial regrowth when using up to 4 orders of magnitude less phage and antibiotic concentrations that were lower than our measured minimum biofilm inhibitory concentration. We did not see a consistent association between phage activity and the evolution of DNS-VISA genotypes in this small number of bacterial strains. IMPORTANCE The extracellular polymeric matrix of biofilms presents an impediment to antibiotic diffusion, facilitating the emergence of multidrug-resistant populations. While most phage cocktails are designed for the planktonic state of bacteria, it is important to take the biofilm mode of growth (the predominant mode of bacterial growth in nature) into consideration, as it is unclear how interactions between any specific phage and its bacterial hosts will depend on the physical properties of the growth environment. In addition, the extent of bacterial sensitivity to any given phage may vary from the planktonic to the biofilm state. Therefore, phage-containing treatments targeting biofilm infections such as catheters and prosthetic joint material may not be merely based on host range characteristics. Our results open avenues to new questions regarding phage-antibiotic treatment efficiency in the eradication of topologically structured biofilm settings and the extent of eradication efficacy relative to the single agents in biofilm populations.

A cationic amphiphilic peptide chaperone rescues Aß42 aggregation and cytotoxicity.

Directing Aß42 to adopt a conformation that is free from aggregation and cell toxicity is an attractive and viable strategy to design therapeutics for Alzheimer's disease. Over the years, extensive efforts have been made to disrupt the aggregation of Aß42 using various types of inhibitors but with limited success. Herein, we report the inhibition of aggregation of Aß42 and disintegration of matured fibrils of Aß42 into smaller assemblies by a 15-mer cationic amphiphilic peptide. The biophysical analysis comprising thioflavin T (ThT) mediated amyloid aggregation kinetic analysis, dynamic light scattering, ELISA, AFM, and TEM suggested that the peptide effectively disrupts Aß42 aggregation. The circular dichroism (CD) and 2D-NMR HSQC analysis reveal that upon interaction, the peptide induces a conformational change in Aß42 that is free from aggregation. Further, the cell assay experiments revealed that this peptide is non-toxic to cells and also rescues the cells from the toxicity of Aß42. Peptides with a shorter length displayed either weak or no inhibitory effect on Aß42 aggregation and cytotoxicity. These results suggest that the 15-residue cationic amphiphilic peptide reported here may serve as a potential therapeutic candidate for Alzheimer's disease.

Lysine-Targeted Reversible Covalent Ligand Discovery for Proteins via Phage Display.

Binding via reversible covalent bond formation presents a novel and powerful mechanism to enhance the potency of synthetic inhibitors for therapeutically important proteins. Work on this front has yielded the anticancer drug bortezomib as well as the antisickling drug voxelotor. However, the rational design of reversible covalent inhibitors remains difficult even when noncovalent inhibitors are available as a scaffold. Herein, we report chemically modified phage libraries, both linear and cyclic, that incorporate 2-acetylphenylboronic acid (APBA) as a warhead to bind lysines via reversible iminoboronate formation. To demonstrate their utility, these APBA-presenting phage libraries were screened against sortase A of Staphylococcus aureus, as well as the spike protein of SARS-CoV-2. For both protein targets, peptide ligands were readily identified with single-digit micromolar potency and excellent specificity, enabling live-cell sortase inhibition and highly sensitive spike protein detection, respectively. Furthermore, our structure-activity studies unambiguously demonstrate the benefit of the APBA warhead for protein binding. Overall, this contribution shows for the first time that reversible covalent inhibitors can be developed via phage display for a protein of interest. The phage display platform should be widely applicable to proteins including those involved in protein-protein interactions.

Eradication of Biofilm-Mediated Methicillin-Resistant Staphylococcus aureus Infections In Vitro: Bacteriophage-Antibiotic Combination.

Bacterial biofilms are difficult to eradicate and can complicate many infections by forming on tissues and medical devices. Phage+antibiotic combinations (PAC) may be more active on biofilms than either type of agent alone, but it is difficult to predict which PAC regimens will be reliably effective. To establish a method for screening PAC combinations against Staphylococcus aureus biofilms, we conducted biofilm time-kill analyses (TKA) using various combinations of phage Sb-1 with clinically relevant antibiotics. We determined the activity of PAC against biofilm versus planktonic bacteria and investigated the emergence of resistance during (24 h) exposure to PAC. As expected, fewer treatment regimens were effective against biofilm than planktonic bacteria. In experiments with isogenic strain pairs, we also saw less activity of PACs against DNS-VISA mutants versus their respective parentals. The most effective treatment against both biofilm and planktonic bacteria was the phage+daptomycin+ceftaroline regimen, which met our stringent definition of bactericidal activity (>3 log10 CFU/mL reduction). With the VISA-DNS strain 8015 and DNS strain 684, we detected anti-biofilm synergy between Sb-1 and DAP in the phage+daptomycin regimen (>2 log10 CFU/mL reduction versus best single agent). We did not observe any bacterial resensitization to antibiotics following treatment, but phage resistance was avoided after exposure to PAC regimens for all tested strains. The release of bacterial membrane vesicles tended to be either unaffected or reduced by the various treatment regimens. Interestingly, phage yields from certain biofilm experiments were greater than from similar planktonic experiments, suggesting that Sb-1 might be more efficiently propagated on biofilm. IMPORTANCE Biofilm-associated multidrug-resistant infections pose significant challenges for antibiotic therapy. The extracellular polymeric matrix of biofilms presents an impediment for antibiotic diffusion, facilitating the emergence of multidrug-resistant populations. Some bacteriophages (phages) can move across the biofilm matrix, degrade it, and support antibiotic penetration. However, little is known about how phages and their hosts interact in the biofilm environment or how different phage+antibiotic combinations (PACs) impact biofilms in comparison to the planktonic state of bacteria, though scattered data suggest that phage+antibiotic synergy occurs more readily under biofilm-like conditions. Our results demonstrated that phage Sb-1 can infect MRSA strains both in biofilm and planktonic states and suggested PAC regimens worthy of further investigation as adjuncts to antibiotics.

Lysine-Targeting Reversible Covalent Inhibitors with Long Residence Time.

We report a new reversible lysine conjugation that features a novel diazaborine product and much slowed dissociation kinetics in comparison to the previously known iminoboronate chemistry. Incorporating the diazaborine-forming warhead RMR1 to a peptide ligand gives potent and long-acting reversible covalent inhibitors of the staphylococcal sortase. The efficacy of sortase inhibition is demonstrated via biochemical and cell-based assays. A comparative study of RMR1 and an iminoboronate-forming warhead highlights the significance and potential of modulating bond dissociation kinetics in achieving long-acting reversible covalent inhibitors.

Causal inference and directed acyclic graph: An epidemiological concept much needed for oral submucous fibrosis.

Oral submucous fibrosis (OSMF), although already established as an oral potentially malignant disorder (OPMD), still stands over a weak bridge because of its controversial pathogenesis. There has been tremendous work on this disease since 1962, surprisingly, we are unsuccessful in finding the exact causation of OSMF. The potential cause for this is either a lack of systematically performed clinical observational studies or over-interpreted inferences of the presented results. Accordingly, the literature is piled with complex data that is being followed by emerging researchers. Hence, this conceptual paper is presented to focus and explain only the epidemiological concepts of causal inference and the construction of DAGs. These concepts will help to encode our subject matter knowledge and assumptions regarding the causal structure problem, classify the source of systematic bias, identify the potential confounders, potential issues in the study design, and guide the data analysis.

Oral submucous fibrosis in children and adolescents: Analysis of 36 cases.

Oral submucous fibrosis (OSMF) is a chronic debilitating irreversible oral potentially malignant disorder affecting any part of the oral cavity. It is usually seen in adults but rarely noticed in children and adolescents. Since the paucity of the cases, there exists a gap of knowledge in the causative habits, root reasons of habit initiation, age of habit initiation, and the common clinical representation of this disorder. The current article aims to bridge this gap by presenting unusual 36 cases of children and adolescents reported at the tertiary care hospital of Vadodara, Gujarat, India, with specific areca nut chewing habit and distinct features of OSMF. Furthermore, the present case series is the first of its kind in the scientific literature with a high number of OSMF cases in children and adolescents.

Structural insight into hybrid peptide ε-helices.

Unique ε-helical organizations (11-helices) from ß,γ-hybrid peptides composed of chiral ß3-amino acids along with achiral 3,3- or 4,4-dimethyl substituted γ-amino acids are disclosed.

Structural Investigation of Hybrid Peptide Foldamers Composed of α-Dipeptide Equivalent ß-Oxy-δ5 -amino Acids.

Due to their equivalent lengths, δ-amino acids can serve as surrogates of α-dipeptides. However, δ-amino acids with proteinogenic side chains have not been well studied because of synthetic difficulties and because of their insolubility in organic solvents. Recently we reported the spontaneous supramolecular gelation of δ-peptides composed of ß(O)-δ5 -amino acids. Here, we report the incorporation of ß(O)-δ5 -amino acids as guests into the host α-helix, α,γ-hybrid peptide 12-helix and their single-crystal conformations. In addition, we studied the solution conformations of hybrid peptides composed of 1:1 alternating α and ß(O)-δ5 -amino acids. In contrast to the control α-helix structures, the crystal structure of peptides with ß(O)-δ5 -amino acids exhibit α-helical conformations consisting of both 13- and 10-membered H-bonds. The α,δ-hybrid peptide adopted mixed 13/11-helix conformation in solution with alternating H-bond directionality. Crystal-structure analysis revealed that the α,γ4 -hybrid peptide accommodated the guest ß(O)-δ5 -amino acid without significant deviation to the overall helix folding. The results reported here emphasize that ß(O)-δ5 -amino acids with proteinogenic side chains can be accommodated into regular α-helix or 12-helix as guests without much deviation of the overall helix folding of the peptides.

Brucellosis in India: results of a collaborative workshop to define One Health priorities.

Brucellosis is an important zoonosis worldwide. In livestock, it frequently causes chronic disease with reproductive failures that contribute to production losses, and in humans, it causes an often-chronic febrile illness that is frequently underdiagnosed in many low- and middle-income countries, including India. India has one of the largest ruminant populations in the world, and brucellosis is endemic in the country in both humans and animals. In November 2017, the International Livestock Research Institute invited experts from government, national research institutes, universities, and different international organizations to a one-day meeting to set priorities towards a "One Health" control strategy for brucellosis in India. Using a risk prioritization exercise followed by discussions, the meeting agreed on the following priorities: collaboration (transboundary and transdisciplinary); collection of more epidemiological evidence in humans, cattle, and in small ruminants (which have been neglected in past research); Economic impact studies, including cost effectiveness of control programmes; livestock vaccination, including national facilities for securing vaccines for the cattle population; management of infected animals (with the ban on bovine slaughter, alternatives such as sanctuaries must be explored); laboratory capacities and diagnostics (quality must be assured and better rapid tests developed); and increased awareness, making farmers, health workers, and the general public more aware of risks of brucellosis and zoonoses in general. Overall, the meeting participants agreed that brucellosis control will be challenging in India, but with collaboration to address the priority areas listed here, it could be possible.

Opportunities for One Health policies to reduce poverty.

Infectious diseases are known to disproportionately affect the poorer sectors of society, particularly those living in low- and middle-income countries. These vulnerable populations battle disease, debt, loss of livelihood and reduced economic well-being with consequences that extend to their families, communities, livestock and the environment. A strong One Health approach is acknowledged as a successful way of enhancing current capacity for the prevention and control of emerging infectious diseases. Furthermore, it is also an effective way to address the multifaceted nuances of poverty. In recognising the interconnectedness of human and animal health with the health of our shared environment, One Health offers a valuable framework to prevent and control emerging infectious diseases through collaboration, coordination and communication across the various sectors involved. In recent years, as examples of One Health implementation have been documented and assessed, the linkages between One Health interventions and poverty alleviation have become more obvious. One Health interventions have the potential to reduce the economic burden of disease and create more efficient systems and approaches that generate higher savings, both direct and indirect, at the human-animal-environment interface. This paper describes aspects of this potential in detail. Although, at present, examples of the relationship between One Health and poverty alleviation are few, they are compelling. The authors believe that they provide persuasive evidence to encourage governments and policy-makers to employ the One Health approach in their efforts to alleviate poverty. Measuring the impact of this link between One Health and poverty alleviation has its constraints since appropriate metrics are still evolving. However, this paper hopes to establish the wisdom of recognising the role that One Health can play in reducing poverty, as well as its capacity to enhance existing policy frameworks.

On sait que les secteurs les plus pauvres de la société subissent de manière disproportionnée l'impact des maladies infectieuses, en particulier dans les pays à revenu faible ou intermédiaire. Ces populations vulnérables sont confrontées à la maladie, à l'endettement, à la perte de leurs moyens de subsistance et à un déficit de bien-être économique dont les effets se perçoivent au niveau des familles et des communautés mais s'étendent également au bétail et à l'environnement. L'approche Une seule santé appliquée avec rigueur est reconnue comme un moyen efficace d'améliorer les capacités actuelles de prévention et de lutte contre les maladies infectieuses émergentes. Elle constitue également un outil puissant pour traiter les différents aspects plurifactoriels de la pauvreté. En prenant en compte l'interconnexion entre la santé humaine et animale et celle de notre environnement commun, Une seule santé fournit un cadre précieux pour prévenir et contrôler les maladies infectieuses émergentes à travers la mise en place d'une collaboration, d'une coordination et d'une communication transversales entre les différents secteurs concernés. Au cours de ces dernières années, l'évaluation et la collecte d'informations sur les exemples de mise en œuvre de l'approche Une seule santé ont fait ressortir les liens entre ces interventions et l'allègement de la pauvreté. Les interventions Une seule santé peuvent réduire le fardeau économique des maladies en créant des approches et des systèmes plus efficients qui permettent de réaliser des économies accrues, tant directes qu'indirectes, à l'interface homme­animal­environnement. Les auteurs décrivent en détail les différents aspects de ce potentiel. Les exemples du lien entre Une seule santé et l'allègement de la pauvreté sont encore peu nombreux mais ils sont probants. Les auteurs estiment apporter une démonstration suffisamment convaincante pour encourager les gouvernements et les décideurs politiques à recourir à l'approche Une seule santé dans le cadre de leurs initiatives de réduction de la pauvreté. La mesure de l'impact du lien entre Une seule santé et l'allègement de la pauvreté reste problématique en raison de l'évolution actuelle des méthodes d'évaluation appropriées. Néanmoins, les auteurs espèrent avoir établi le bien-fondé du rôle que peut jouer Une seule santé dans la réduction de la pauvreté ainsi que sa capacité d'améliorer les cadres politiques existants.

Se sabe que las enfermedades infecciosas afectan de forma desproporcionada a los sectores pobres de la sociedad, especialmente en los países de renta baja o mediana. Estas poblaciones vulnerables libran batalla a la enfermedad, las deudas, la pérdida de sus medios de vida y la merma de su bienestar económico con consecuencias que se extienden a su familia, su comunidad, su ganado y el medio ambiente. También está comprobado que una firme apuesta por la filosofía de Una sola salud es un expediente fructífero para mejorar la actual capacidad de prevención y control de enfermedades infecciosas emergentes. Se trata además de un medio eficaz para combatir la pobreza en sus múltiples facetas. Partiendo de la evidencia de la conexión recíproca existente entre salud humana, sanidad animal y el medio ambiente que todos compartimos, la noción de Una sola salud ofrece un valioso marco de referencia desde el que prevenir y combatir las enfermedades infecciosas emergentes gracias a la colaboración, coordinación y comunicación entre los distintos sectores interesados. De unos años a esta parte, a medida que se llevaban adelante y se describían experiencias de aplicación práctica de esta filosofía, ha ido quedando claro el nexo entre las intervenciones realizadas en clave de Una sola salud y la mitigación de la pobreza. Este tipo de intervenciones ofrecen la posibilidad de reducir el fardo económico que suponen las enfermedades y de propiciar sistemas y soluciones más eficaces y que generen un mayor ahorro, tanto directo como indirecto, en la interfaz del ser humano, los animales y el medio ambiente. Los autores describen en detalle una serie de aspectos del potencial que encierran esas intervenciones. Los ejemplos de la relación existente entre Una sola salud y la mitigación de la pobreza, aunque a día de hoy son contados, no dejan de resultar elocuentes. Los autores entienden que los datos expuestos son lo bastante convincentes como para alentar a gobiernos y planificadores de políticas a trabajar desde la óptica de Una sola salud para combatir la pobreza. Cuantificar los efectos de este nexo entre Una sola salud y mitigación de la pobreza no es tarea fácil, por cuanto las herramientas métricas necesarias aún están en plena gestación. Con todo, los autores esperan que el artículo avale la sabia conclusión de que los principios de Una sola salud pueden ser útiles para reducir la pobreza y también para perfeccionar los marcos de políticas existentes hoy en día.

Divergent Supramolecular Gelation of Backbone Modified Short Hybrid δ-Peptides.

The ordered supramolecular assemblies of short peptides have been recently gaining momentum due to their widespread applications in biology and materials sciences. In contrast to the α-peptides, limited success has been achieved from the backbone modified peptides. The proteolytic stability and conformational flexibility of the backbone modified peptides composed of ß-, γ-, and δ-amino acids can be explored to design ordered supramolecular gels and self-assembled materials. In this article, we are reporting the divergent supramolecular gels from a new class of short hybrid dipeptides composed of conformationally flexible new ß(O)-δ5-amino acids. The hybrid dipeptide composed of ß3- and ß(O)-δ5-Phe showed the formation of transparent gels from the aromatic solvents, while the dipeptide composed of ß(O)-δ5-Phe showed the thixotropic gel in phosphate buffered saline (PBS). In contrast, no organic or hydrogels were observed from the dipeptides composed of alternating α- and ß(O)-δ5-Phe as well as γ4 and ß(O)-δ5-Phe. The organogelation property displayed by the ß3,ß(O)-δ5-Phe dipeptide was further explored to recover the oil spills from the oil-water mixture. The thixotropic hydrogels displayed by the ß(O)-δ5, ß(O)-δ5-Phe dipeptide was further utilized as matrix along with cell culture medium to grow the cells in 2D-cell culture. Replacing the backbone -CH2- with "O" in the δ-Phe leads to the drastic change in the supramolecular behavior of δ-peptides. Overall, the short dipeptides from different backbone modified amino acids showed the divergent gelation properties and these properties can be further explored to design new functional biomaterials.

Systematic review of preoperative carotid duplex ultrasound compared with computed tomography carotid angiography for carotid endarterectomy.

INTRODUCTION: We reviewed the literature for preoperative computed tomography carotid angiography and/or carotid duplex to determine their respective sensitivity and specificity in assessing the degree of carotid stenosis. We aimed to identify whether one imaging modality can accurately identify critical stenosis in patients presenting with transient ischaemic attack or symptoms of a cerebrovascular accident requiring carotid endarterectomy. METHODS: Systematic search of MEDLINE, Embase, Cochrane database of systematic reviews, all Evidence-Based Medicine Reviews (Cochrane Database of Systematic Reviews, ACP Journal club, Database of Abstracts of Reviews of Effects, Cochrane Clinical Answers, Cochrane Controlled Trials Register, Cochrane Methodology Register, Health Technology Assessment and NHS Economic Evaluation Database) for primary studies relating to computed tomography carotid angiography (CTA) and/or carotid duplex ultrasound (CDU). Studies included were published between 1990 and 2018 and focused on practice in the UK, Europe and North America. RESULTS: The sensitivity and specificity of CTA and CDU are comparable. CDU is safe and readily available in the clinical environment hence its use in the initial preoperative assessment of carotid stenosis. CDU is an adequate imaging modality for determining stenosis greater than 70%; sensitivity and specificity are improved when the criteria for determining greater than 70% stenosis are adjusted. Vascular laboratories opting to use duplex as their sole imaging modality should assess the sensitivity and specificity of their own duplex procedure before altering practice to preoperative single imaging for patients. CONCLUSIONS: The sensitivity and specificity of CTA (90.6% and 93%, respectively) and CDU (92.3% and 89%, respectively) are comparable. Both are dependent on criteria used in vascular laboratories. CDU sensitivity and specificity was improved to 98.7% and 94.1%, respectively, where peak systolic velocity and end diastolic velocity were assessed. Either modality can be used to determine greater than 70% stenosis, although a secondary imaging modality may be required for cases of greater than 50% stenosis.

Artificial ß-Double Helices from Achiral γ-Peptides.

Double helices are not common in polypeptides and proteins except in the peptide antibiotic gramicidin A and analogous l,d-peptides. In contrast to natural polypeptides, remarkable ß-double-helical structures from achiral γ-peptides built from α,ß-unsaturated γ-amino acids have been observed. The crystal structures suggest that they adopted parallel ß-double helical structures and these structures are stabilized by the interstrand backbone amide H-bonds. Furthermore, both NMR spectroscopy and fluorescence studies support the existence of double-helical conformations in solution. Although a variety of folded architectures featuring distinct H-bonds have been discovered from the ß- and γ-peptide foldamers, this is the first report to show that achiral γ-peptides can spontaneously intertwine into ß-double helical structures.

Chemoselective Nitrile Oxide-Alkyne 1,3-Dipolar Cycloaddition Reactions from Nitroalkane-Tethered Peptides.

Synthesis and incorporation of a new amino acid with a nitroalkane side chain into peptides, in situ transformation of a nitroalkane side chain into nitrile oxide, and chemoselective 1,3-dipolar cycloaddition reactions between in situ generated nitrile oxide and different alkynes are reported. The nitroalkane-mediated nitrile oxide-alkyne cycloaddition was found to be orthogonal to the copper(I)-catalyzed azide-alkyne cycloaddition reaction. The combination of orthogonal nitrile oxide-alkyne and azide-alkyne cycloaddition reactions can be explored to tailor different 1,2,3-triazole and 3,5-isoxazoles, respectively, on the peptide backbone.

Exploring structural features of folded peptide architectures in the construction of nanomaterials.

We are reporting the influence of foldamer structures on their self-assembled architectures. In a sharp contrast to the ordered α,γ-hybrid 12-helix obtained from 1 : 1 alternating Aib and γ-Phe, the α,γ-hybrid peptides constituted with α-Phe and 4,4-dimethyl γ-amino acid (Aic) displayed the extended sheet type of conformations in solution and spontaneously self-assembled into thermally and proteolytically stable capsules. In contrast, the conformationally ordered 12-helix self-assembled into a three-dimensional supramolecular polyhedron.

pH sensitive coiled coils: a strategy for enhanced liposomal drug delivery.

Stimuli responsive controlled release from liposome based vesicles is a promising strategy for the site specific delivery of drugs. Herein, we report the design of pH sensitive coiled coils and their incorporation into the liposome as triggers for the controlled release of encapsulated drugs. The designed coiled coil peptides with the incorporation of environment sensitive fluorescent amino acids were found to be stable at physiological pH and unstructured while changing the pH of the environment to either acidic or basic. This pH dependent conformational switch of the coiled-coil polypeptides was exploited as triggers for the enhanced release of the encapsulated drug molecules from liposomes. The SEM, DLS and TEM analysis revealed the uniform morphology of the peptide liposome hybrid vesicles. Further, the drug encapsulated liposome internalization experiments with cancer cells revealed the enhanced release and accumulation of drugs in the acidic lysosomal compartments in comparison with liposomes without coiled coils.

Presenting symptoms of glioma in adults.

OBJECTIVE: Studies on the presenting symptoms of glioma in adults in the age of readily available MRI imaging are scarce. This study investigates presenting symptoms of glioma and assesses the correlations of the presenting symptoms with patient age and histopathological class of the tumor. MATERIALS AND METHODS: A retrospective review of the medical records of histologically verified glioma patients treated in Turku University Hospital, during 2006-2010, was conducted. The associations between the presenting symptoms and other covariates were assessed individually. RESULTS: One hundred and fifty patients were ascertained. The most common presenting symptoms of glioma were seizure and cognitive disorder. Patients presenting with seizures were younger than patients with cognitive disorders, and the grade of the tumor was also found to significantly correlate with the most common presenting symptoms. Age group and tumor grade were statistically significant factors of cognitive disorder (P = 0.0037 and P = 0.0069) and age group of seizure (P = 0.0065). The associations between the presenting symptoms and the anatomical location, spread into adjacent brain areas, or laterality of the tumor or site of diagnosis were found to be statistically insignificant. Headache was not a common presenting symptom in glioma patients. CONCLUSIONS: The main presenting symptoms of glioma in adults in the MRI age still are seizures and cognitive disorder. Patient age and tumor grade correlate positively with the incidence of cognitive disorder and patient age negatively with incidence of seizure as a presenting symptom. Headache is an uncommon manifestation and does not appear as a sole symptom.