Search

Hydrophilic peptides constitute most of the active peptides. They mostly permeate via tight junctions (paracellular pathway) in the intestine. This permeability mechanism restricts the magnitude of their oral absorption and bioavailability. We hypothesized that concealing the hydrophilic residues of the peptide using the lipophilic prodrug charge masking approach (LPCM) can improve the bioavailability of hydrophilic peptides. To test this hypothesis, a cyclic N-methylated hexapeptide containing Arg-Gly-Asp (RGD) and its prodrug derivatives, masking the Arg and Asp charged side chains, were synthesized. The library was evaluated for intestinal permeability in vitrousing the Caco-2 model. Further investigation of metabolic stability ex vivo models in rat plasma, brush border membrane vesicles (BBMVs), and isolated CYP3A4 microsomes and pharmacokinetic studies was performed on a selected peptide and its prodrug (peptide 12). The parent drug analogues were found to have a low permeability rate in vitro, corresponding to atenolol, a marker for paracellular permeability. Moreover, palmitoyl carnitine increased the Pappof peptide 12by 4-fold, indicating paracellular permeability. The Pappof the prodrug derivatives was much higher than that of their parent peptides. For instance, the Pappof the prodrug 12Pwas 20-fold higher than the Pappof peptide 12in the apical to basolateral (AB) direction. Whereas the permeability in the opposite direction (BA of the Caco-2 model) was significantly faster than the PappAB, indicating the involvement of an efflux system. These results were corroborated when verapamil, a P-gp inhibitor, was added to the Caco-2 model and increased the PappAB of prodrug 12Pby 3-fold. The prodrug 12Pwas stable in the BBMVs environment, yet degraded quickly (less than 5 min) in the plasma into the parent peptide 12. Pharmacokinetic studies in rats showed an increase in the bioavailability of peptide 12> 70-fold (from 0.58 ± 0.11% to 43.8 ± 14.9%) after applying the LPCM method to peptide 12and converting it to the prodrug 12P. To conclude, the LPCM approach converted the absorption mechanism of the polar peptides from a paracellular to transcellular pathway that tremendously affects their oral bioavailability. The LPCM method provides a solution for the poor bioavailability of RGD cyclohexapeptides and paves the way for other active hydrophilic and charged peptides with poor oral bioavailability.

ABSTRACTBackground:Transcatheter aortic valve implantation (TAVI) is the treatment of choice in patients with severe symptomatic aortic stenosis and high surgical risk. Ventricular septal defect (VSD) is a rare complication of TAVI acquired peri-procedurally. This study examines the incidence and possible mechanisms of TAVI-associated VSD.Methods:A multicenter, retrospective study of 400 patients who underwent TAVI in 2015 was conducted. All patients were evaluated with transthoracic echocardiography before and after the procedure.Results:Six subjects (1.5%) were found to have new VSD. Five of them had severe aortic valve calcification. Three patients (50%) were implanted with the Sapien valve (Edwards Lifesciences, Irvine, CA, USA) and the other three with Corevalve valve (Medtronic, Minneapolis, MN, USA). Four patients had a membranous type of VSD, and two patients had a muscular type apical VSD. All six cases were diagnosed to have a small, restrictive left to right shunt, with minimal hemodynamic significance. The patients were not symptomatic and therefore did not require any further intervention. Two mechanisms are proposed for VSD formation: pressure exerted directly by the valve on the membranous septum, and penetration of the apical septum by the stiff wire.Conclusion:VSD is a rare complication of TAVI that may involve the membranous or the muscular interventricular septum. Hemodynamic and clinical sequelae are mostly benign. Proper imaging techniques and proper devices to further decrease VSD formation incidence post-TAVI have yet to be determined.

Protein-protein Interactions (PPIs) are particularly important for controlling both physiologic and pathologic biological processes but are difficult to target due to their large and/or shallow interaction surfaces unsuitable for small molecules. Linear peptides found in nature interact with some PPIs, and protein active regions can be used to design synthetic peptide compounds for inhibition of PPIs. However, linear peptides are limited therapeutically by poor metabolic and conformational stability, which can compromise their bioactivity and half-life. Cyclic peptidomimetics (modified peptides) can be used to overcome these challenges because they are more resistant to metabolic degradation and can be engineered to adopt desired conformations. Backbone cyclization is a strategy that we developed to improve drug-like properties of linear peptide leads without jeopardizing the integrity of functionally relevant side-chains. Here, we provide the first description of an entire approach for developing backbone cyclized peptide compounds, based upon two straightforward ‘ABC’ and ‘DEF’ processes. We present practical examples throughout our discussion of revealing active regions important for PPIs and identifying critical pharmacophores, as well as developing backbone cyclized peptide libraries and screening them using cycloscan. Finally, we review the impact of these advances and provide a summary of current ongoing work in the field.

Background This study examined the association between cardiac structure and function and the deterioration in activities of daily living (ADLs) in an age-homogenous, community-dwelling population of patients born in 1920–1921 over a five-year follow-up period.Design Longitudinal cohort study.Methods Patients were recruited from the Jerusalem Longitudinal Cohort Study, which has followed an age-homogenous cohort of Jerusalem residents born in 1920–1921. Patients underwent home echocardiography and were followed up for five years. Dependence was defined as needing assistance with one or more basic ADL. Standard echocardiographic assessment of cardiac structure and function, including systolic and diastolic function, was performed. Reassessment of ADLs was performed at the five-year follow-up.Results A total of 459 patients were included in the study. Of these, 362 (79%) showed a deterioration in at least one ADL at follow-up. Patients with functional deterioration had a significantly higher left ventricular mass index and left atrial volume with a lower ejection fraction. There was no significant difference between the diastolic parameters the groups in examined. When the data were examined categorically, a significantly larger percentage of patients with functional decline had an abnormal left ventricular ejection fraction and left ventricular hypertrophy. The association between left ventricular mass index and functional decline remained significant in all multivariate models.Conclusions In this cohort of the oldest old, an elevated left ventricular mass index, higher left atrial volumes and systolic, but not diastolic dysfunction, were predictive of functional disability.

Building accurate rainfall–runoff models is an integral part of hydrological science and practice. The variety of modeling goals and applications have led to a large suite of evaluation metrics for these models. Yet, hydrologists still put considerable trust into visual judgment, although it is unclear whether such judgment agrees or disagrees with existing quantitative metrics. In this study, we tasked 622 experts to compare and judge more than 14,000 pairs of hydrographs from 13 different models. Our results show that expert opinion broadly agrees with quantitative metrics and results in a clear preference for a Machine Learning model over traditional hydrological models. The expert opinions are, however, subject to significant amounts of inconsistency. Nevertheless, where experts agree, we can predict their opinion purely from quantitative metrics, which indicates that the metrics sufficiently encode human preferences in a small set of numbers. While there remains room for improvement of quantitative metrics, we suggest that the hydrologic community should reinforce their benchmarking efforts and put more trust in these metrics. A group of 622 participants visually judge model simulations similarly to quantitative metrics and considers a Machine Learning model bestNash–Sutcliffe efficiency and Kling–Gupta efficiency are good predictors of overall and high‐flow hydrograph quality but low‐flow metrics are poor predictors of low‐flow qualityWe can discriminate hydrographs that experts consistently consider good or bad purely based on existing quantitative metrics A group of 622 participants visually judge model simulations similarly to quantitative metrics and considers a Machine Learning model best Nash–Sutcliffe efficiency and Kling–Gupta efficiency are good predictors of overall and high‐flow hydrograph quality but low‐flow metrics are poor predictors of low‐flow quality We can discriminate hydrographs that experts consistently consider good or bad purely based on existing quantitative metrics

AbstractContext:Urothelial carcinoma (UC) is common and highly recurrent. Diagnosis and follow-up involve invasive cystoscopies.Objective:To evaluate H19RNA in urine cells as diagnostic tool for UC.Materials and methods:RT-PCR analysis of urine samples from healthy volunteers and UC patients.Results:H19RNA was unequivocally detected in the urine of 90.5% of patients and 25.9% of controls. H19copies were three orders of magnitude higher in patients. Receiver operating characteristic analysis showed an area under the curve of 0.933.Conclusions:This pilot study shows that urinary cell H19is a highly sensitive test for UC and pending verification could transform patient management.

Background: What is neural memory? How does it differ from binary encoded, computer memory? Attempts to model brain function using contemporary computer hardware and (information) theory suggests the need for a new paradigm. The disparity between (dry) electronic devices that “compute” in binary format (n=2) and biologic (wet) neural nets that mentate in “multinary” format (i.e. n>10), reflects drastically differing recall systems. Focusing on codes, we discuss Morse and Braille codes and note that a binary bit (0 /1) cannot encode a psychic (emotive) state. Between 0 and 1, there is no code for “emotions”. Hypothesis: “Form follows function”. There are no “naked neurons”. Neuron morphology (extended shape, large surface area) implies intimate contact with its surroundings. Based on observed morphological and biochemical evidence, we propose a tripartite, biochemical process for encoding neural memory, whereby the surrounding “neural extracellular matrix” (nECM), functions as a “memory material” to encode and store cognitive units of information (cuinfo). The dopants (>10 neuro-metals, >90 neuro-transmitters (NTs)) within vesicles ejected by neurons into the nECM, provide the neuron with Avogadro scale (A=6x10 23 ) “dopants” for encoding emotive memory. Calculations using experimentally determined (molar) levels of metals and NTs, reveal astronomical coding options and capacity. Conclusion: Neurons collectively generate memory, using both electrodynamic and chemodynamic signals. The NTs link physiology to psyche, functioning in memory as signifiers (enciphers) of emotions. An algorithm, blueprint, calculus, fractal, mimetic or simulation that ignores {neuron-nECM-NT} interactions, cannot emulate mental processes of the brain, recalling emotive memory to survive.

Solid-phase methodology was used to synthesize a series of fully reduced linear oligolysines (pseudooligolysines, abbreviated herein as PLs) containing up to five adjacent CH₂NH peptide bond isosteres. The reduced peptide bonds were introduced by the reductive alkylation reaction between Fmoc-Lys-(Boc)-al and a free α-amine moiety on the pseudopeptidyl resin, using sodium cyanoborohydride in an acidified mixture of NMP/CH₃OH (1 : 1 v/v). The oligomeric molecules, which can be regarded as polyethylene imine and spermine analogs, possess multiple positive charges under physiological conditions and form tight complexes with plasmid DNA. These characteristics and the increased resistance to hydrolysis by trypsin make these molecules potential candidates for future use as DNA carriers in gene delivery.

Background:People over the age of 85 are the world's most rapidly growing age group and have a high incidence of cardiovascular mortality. Ejection fraction (EF), the most commonly used index of systolic function, may be limited prognostically in this population given the high incidence of left ventricular hypertrophy and myocardial contraction fraction (MCF) may be more accurate. The objective of this longitudinal study was to assess the prognosis of MCF in an age-homogenous, community-dwelling population of subjects.Methods:Subjects were recruited from the Jerusalem Longitudinal Cohort Study. Echocardiography was performed with a portable echocardiograph at the subjects place of residence. Standard echocardiographic assessment of cardiac structure and function including MCF was performed. 5-year mortality was assessed via a centralized government database.Results:418 subjects (197 males, 218 females) were enrolled in the study of whom 113 (27%) died at the time of 5-year follow-up. Subjects who died had significantly lower MCF (32 ± 14% vs. 36 ± 12%; p < 0.004) and EF (51.6 ± 11.6% vs 56.3 ± 9.4%; p< 0.0001) than survivors. On Kaplan-Meier analysis MCF was more significantly associated with mortality than EF (p< 0.0005 vs p < 0.04). The association between MCF and mortality remained significant on multivariate analysis as both a categorical and continuous variable while EF was only significant as a continous variable.Conclusions:MCF assessed by home echocardiography provides additional prognostic information to EF and may be a superior predictor of 5-year mortality in a community-dwelling population of the oldest old.

In vitro studies suggested that circulating inflammatory cytokines cause septic myocardial dysfunction. However, no in vivo clinical study has investigated whether serum inflammatory cytokine concentrations correlate with septic myocardial dysfunction.

We report on in situ, self-assembly, solution-processing of metallic (Au/Ag) nanowire-based transparent electrodes integrated to vertical organic field-effect transistors (VOFETs). In the VOFET architecture, the nanowires’ microstructure facilitates current modulation by the gate across the otherwise shielding sandwiched source electrode. We show N-type VOFETs operation with on/off ratio ∼1 × 105and high current density (>1 mA cm–2at VDS= 5 V). The integration of the device design and the transparent electrode deposition methods offers a potential route for all-solution processing-based, large-area, high-efficiency organic electronics.