A coarse-grained Molecular Dynamics study of phase behavior in Co-assembled lipomimetic oligopeptides.

Multicomponent biomolecular aggregates, i.e., systems consisting of more than one type of biomolecular component co-assembling into one aggregate, provide an interesting design space for engineering unique biomaterials. In this study, we examine the co-assembly of two lipomimetic oligopeptide block copolymers selected for their lipid-like amphiphilicity and highly similar architectures into nanofibers via coarse-grained MD simulations. We focus on the behavior of these peptides due to incremental differences in size by selecting two peptides that differ in length by exactly one amino acid residue. We find that the longer peptide sequence displays greater self-association properties.

Peptide-based vesicles and droplets: a review.

Peptide assembly is an increasingly important field of study due to the versatility, tunability and vast design space of amino acid based biomolecular assemblies. Peptides can be precisely engineered to possess various useful properties such as the ability to form supramolecular assemblies, desired response to pH, or thermal stability. These peptide supramolecular assemblies have diverse morphologies including vesicles, nanotubes, nanorods and ribbons. Of specific interest is the domain of engineering peptides that aggregate into spherical nanostructures due to their encapsulation properties: the ability to hold, transport and release chemical payloads in a controllable manner. This is invaluable to the fields of nanomedicine and targeted drug delivery. In this review, the state of the art in the domain of peptide-based vesicles and nanospheres is summarized. Specifically, an overview of the assembly of peptides into nanovesicles and nanospheres is provided. Both aromatic as well as aliphatic side chain amino acids are discussed. The domain of aromatic side chained amino acid residues is largely dominated by phenylalanine based peptides and variants thereof. Tyrosine also demonstrates similar aggregation properties. Both experimentally and computationally driven approaches are discussed. The domain of aliphatic amino acid residues based vesicles and droplets is broader, and details multiple amino acid residues such as alanine, valine, lysine, glycine, proline, and aspartic acid. Finally, a discussion on potential future directions is provided.

Sedimentation Velocity and Potential in Dilute Suspensions of Charge-Regulating Porous Spheres.

The sedimentation of a charge-regulating porous sphere surrounded by an arbitrary electric double layer, which usually models a permeable polyelectrolyte coil or an aggregate of nanoparticles, is analyzed for the first time. The hydrodynamic frictional segments and ionogenic functional groups uniformly distribute in the porous sphere, and a regulation mechanism for the dissociation and association reactions occurring at these functional groups linearly relates the local electric potential to fixed charge density. The linearized electrokinetic equations governing the ionic concentration (or electrochemical potential energy), electric potential, and fluid velocity fields are solved for the case of a small basic fixed charge density by the regular perturbation method. Analytical formulae for the sedimentation velocity of a porous sphere and sedimentation potential of a dilute suspension of porous spheres are then obtained. The charge regulation tends to reduce the electrokinetic retardation to sedimentation velocity and the sedimentation potential (can be as much as 50 and 25%, respectively) compared to the case that the fixed charge density is a constant. Both the electrokinetic retardation to sedimentation velocity and the sedimentation potential vanish at the isoelectric point of the particles. The increase in the bulk concentration of the potential-determining ions crossing the isoelectric point changes signs of the fixed charges and thus causes a reversal in the direction of the sedimentation potential. The effects of charge regulation on the sedimentation of porous particles differ substantially from those of hard particles.

Nucleic Acid Tests for BK Polyomavirus Is Critical in Renal Transplant Recipients.

This study evaluates the incidence of BK polyomavirus (BKV) and prognosis of BKV infection in kidney transplant recipients (KTRs) who received transplantation in our hospital before and after regular BKV nucleic acid test (NAT) was implemented. METHODS: The study included 74 KTRs who received a single kidney either from standard- or expanded-criteria deceased donor between March 2011 and March 2017. BKV NATs were regularly checked in 26 patients (group 1) in the first posttransplant year in accordance with current guidelines since NAT was implemented in our laboratory in 2014. We retrospectively compared 48 KTRs (group 2) who either received NAT when necessary in another laboratory or were not checked before 2014. RESULTS: There was no significant difference in patient characteristics between groups. BKV viruria were confirmed in 8 of 26 (30.8%) group 1 patients, whereas only 2 of 48 (4.2%) BKV infections were confirmed in group 2. None of the BKV(+) KTRs in group 1 developed BK polyomavirus-associated nephropathy (BKVAN), whereas 2 BKV(+) patients (100%) of group 2 developed BKVAN, which indicates renal function deterioration and biopsy-validated nephropathy. There was no significant difference in graft survival and renal function between the 2 groups. CONCLUSIONS: The risk of BKV infection is considerably higher in KTRs using NAT. Because there is no approval treatment, early diagnosis of BKV infection and early reduction of immunosuppression agents is critical for KTRs. Implementation of regular BKV NAT is mandatory before BKVAN and malignant neoplasms develop.

Discovery and development of next generation sGC stimulators with diverse multidimensional pharmacology and broad therapeutic potential.

Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC), an enzyme that catalyzes the conversion of guanosine-5'-triphosphate (GTP) to cyclic guanosine-3',5'-monophophate (cGMP), transduces many of the physiological effects of the gasotransmitter NO. Upon binding of NO to the prosthetic heme group of sGC, a conformational change occurs, resulting in enzymatic activation and increased production of cGMP. cGMP modulates several downstream cellular and physiological responses, including but not limited to vasodilation. Impairment of this signaling system and altered NO-cGMP homeostasis have been implicated in cardiovascular, pulmonary, renal, gastrointestinal, central nervous system, and hepatic pathologies. sGC stimulators, small molecule drugs that synergistically increase sGC enzyme activity with NO, have shown great potential to treat a variety of diseases via modulation of NO-sGC-cGMP signaling. Here, we give an overview of novel, orally available sGC stimulators that Ironwood Pharmaceuticals is developing. We outline the non-clinical and clinical studies, highlighting pharmacological and pharmacokinetic (PK) profiles, including pharmacodynamic (PD) effects, and efficacy in a variety of disease models.

Comparative effect of antipsychotics on risk of self-harm among patients with schizophrenia.

OBJECTIVE: To investigate the association of different antipsychotic treatments with hospitalization due to self-harm among patients with schizophrenia. METHOD: This retrospective cohort study was based on Taiwan's universal health insurance database. Patients aged 15-45 years with a newly diagnosed schizophrenic disorder in 2001-2012 were included. The study outcome was the first hospitalization due to self-harm or undetermined injury after the diagnosis of schizophrenic disorders. The exposure status of antipsychotics was modeled as a time-dependent variable. The analyses were stratified by antipsychotic dosage based on defined daily dose (DDD). RESULTS: Among 70 380 patients with a follow-up of 500 355 person-years, 2272 self-harm hospitalization episodes were identified. Compared with none or former use, current use of several second-generation antipsychotics with a dose of one DDD or above, including amisulpride, aripiprazole, clozapine, risperidone, and sulpiride, was associated with decreased risk of self-harm hospitalization, with clozapine showing the strongest effect (adjusted rate ratio = 0.26, 95% confidence interval 0.15-0.47). CONCLUSION: The protective effect on self-harm may vary across different antipsychotics. Further studies are needed to replicate the findings.

Polygenic risk for schizophrenia and neurocognitive performance in patients with schizophrenia.

Both neurocognitive deficits and schizophrenia are highly heritable. Genetic overlap between neurocognitive deficits and schizophrenia has been observed in both the general population and in the clinical samples. This study aimed to examine if the polygenic architecture of susceptibility to schizophrenia modified neurocognitive performance in schizophrenia patients. Schizophrenia polygenic risk scores (PRSs) were first derived from the Psychiatric Genomics Consortium (PGC) on schizophrenia, and then the scores were calculated in our independent sample of 1130 schizophrenia trios, who had PsychChip data and were part of the Schizophrenia Families from Taiwan project. Pseudocontrols generated from the nontransmitted parental alleles of the parents in these trios were compared with alleles in schizophrenia patients in assessing the replicability of PGC-derived susceptibility variants. Schizophrenia PRS at the P-value threshold (PT) of 0.1 explained 0.2% in the variance of disease status in this Han-Taiwanese samples, and the score itself had a P-value 0.05 for the association test with the disorder. Each patient underwent neurocognitive evaluation on sustained attention using the continuous performance test and executive function using the Wisconsin Card Sorting Test. We applied a structural equation model to construct the neurocognitive latent variable estimated from multiple measured indices in these 2 tests, and then tested the association between the PRS and the neurocognitive latent variable. Higher schizophrenia PRS generated at the PT of 0.1 was significantly associated with poorer neurocognitive performance with explained variance 0.5%. Our findings indicated that schizophrenia susceptibility variants modify the neurocognitive performance in schizophrenia patients.

Recovery after PILP remineralization of dentin lesions created with two cariogenic acids.

OBJECTIVES: Acetate and lactate are important cariogenic acids produced by oral bacteria. They produced different residual dentin structures in artificial lesions of similar depth. We evaluated if such lesions responded in the same way to a polymer-induced-liquid-precursor (PILP) remineralization. DESIGN: Dentin blocks obtained from human third molars, divided into 6 groups (n=3). Blocks were demineralized with acetate (66h) or lactate (168h) buffer at pH 5.0 to create 140µm target lesion depths. A-DEM and L-DEM groups received no remineralization. Other groups were remineralized for 14days. 100µg/mL polyaspartate was added into the remineralizing buffer for A-PIL and L-PIL, whereas A-CAP and L-CAP were treated with the same solution but without polyaspartate. Cross-sectioned blocks were examined for shrinkage and AFM-topography. Line profiles of reduced elastic modulus (Er) were obtained by AFM-based nanoindentation across the lesion. Ultrastructures were examined with TEM. RESULTS: A-PIL and L-PIL recovered in shrinkage to the original height of the dentin and it appeared normal with tubules, with increases in Er at both outer flat and inner sloped zones. At the sloped zone, acetate lesions lost more Er but recovery rate after PILP was not statistically different from lactate lesions. A-CAP and L-CAP showed surface precipitates, significantly less recovery in shrinkage or Er as compared to PILP groups. TEM-ultrastructure of PILP groups showed similar structural and mineral components in the sloped zone for lesions produced by either acid. CONCLUSIONS: The PILP process provided significant recovery of both structure and mechanical properties for artificial lesions produced with acetate or lactate.

Depicting Binding-Mediated Translocation of HIV-1 Tat Peptides in Living Cells with Nanoscale Pens of Tat-Conjugated Quantum Dots.

Cell-penetrating peptides (CPPs) can translocate across cell membranes, and thus have great potential for the cellular delivery of macromolecular cargoes. However, the mechanism of this cellular uptake process is not yet fully understood. In this study, a time-lapse single-particle light-sheet microscopy technique was implemented to obtain a parallel visualization of the translocating process of individual human immunodeficiency virus 1 (HIV-1) transactivator of transcription (Tat) peptide conjugated quantum dots (TatP-QDs) in complex cellular terrains. Here, TatP-QDs served as nanoscale dynamic pens, which depict remarkable trajectory aggregates of TatP-QDs on the cell surface. Spectral-embedding analysis of the trajectory aggregates revealed a manifold formed by isotropic diffusion and a fraction of directed movement, possibly caused by interaction between the Tat peptides and heparan sulfate groups on the plasma membrane. Further analysis indicated that the membrane deformation induced by Tat-peptide attachment increased with the disruption of the actin framework in cytochalasin D (cyto D)-treated cells, yielding higher interactions on the TatP-QDs. In native cells, the Tat peptides can remodel the actin framework to reduce their interaction with the local membrane environment. Characteristic hot spots for interaction were detected on the membrane, suggesting that a funnel passage may have formed for the Tat-coated particles. This finding offers valuable insight into the cellular delivery of nanoscale cargo, suggesting an avenue for direct therapeutic delivery.

[Historical review on obstructive sleep apnea in children]. / Revue historique sur le syndrome d'apnée obstructive du sommeil chez l'enfant.

An historical review on the discoveries on pediatric obstructive sleep apnea syndrome and sleep-disordered breathing is outlined. Starting with the description by Dickens of "Joe" the obese, snoring and sleepy individual, the authors trace more than 50 years of questions and research starting with the lean adult to the child and from the recognition of obstructive sleep apnea syndrome to the outline of upper-airway resistance syndrome. The pathophysiological knowledge on sleep-disordered breathing has evolved over time, as have treatment approaches in children, from tracheostomy to positive-airway-pressure therapy, to adenotonsillectomy with and without orthodontic treatments to oral-facial myofunctional therapy. Co-morbidities of sleep-disordered breathing are multiple, involving cognition, behavioral, and mood disorders, cardiovascular impairment, etc. There have been many advances in a short time due to the investigation of OSAS, but many questions still need responses.

Effect of kinesiology taping on hemiplegic shoulder pain and functional outcomes in subacute stroke patients: a randomized controlled study.

BACKGROUND: Hemiplegic shoulder pain (HSP) impedes functional motor recovery of the affected limbs and negatively affects quality of life and daily activities. Kinesiology taping (KT) may provide improvement in hemiplegic shoulder pain and upper extremity function after an acute stroke. AIM: To assess the impact of KT on HSP, upper extremity functional outcomes, and the prevention of shoulder soft tissue injury in subacute stroke patients with hemiplegic shoulders during rehabilitation. DESIGN: Randomized, double-blind controlled trial. SETTING: Rehabilitation unit at a single medical center. POPULATION: Forty-four subacute stroke patients with hemiplegia. METHODS: Forty-four subacute stroke patients with hemiplegia participated in this study and were randomly allocated to the control group (sham KT) or experimental group (therapeutic KT). In the experimental group, a 3-week therapeutic KT with conventional inpatient rehabilitation was applied for 5 days per week. In the control group, the patients received a 3-week sham KT with conventional inpatient rehabilitation for 5 days per week. Shoulder subluxation, spasticity, hemiplegic shoulder pain, the Fugl-Meyer Assessment for Upper Extremity (FMA-UE), modified Barthel Index (MI), Stroke-Specific Quality of Life (SSQOL) scale, and shoulder sonography were measured before and after treatment. RESULTS: Pain-free flexion was significantly increased in hemiplegic shoulders after therapeutic KT. From 16 (70%) to 20 (87%) patients in the control and from 12 (57%) to 12 (57%) in the experimental groups had HSP after intervention, and a significant difference in the occurrence of HSP was found between these groups after treatment (P<0.05). Significant improvements (P<0.05) were noted in the FMA-UE, modified BI, and SSQOL scales after treatment in both groups. No significant differences between the groups were seen on shoulder sonography (P>0.05). CONCLUSIONS: Therapeutic KT may limit the development of HSP and improve shoulder flexion in subacute stroke patients with flaccid shoulders during inpatient rehabilitation. For subacute stroke patients with hemiplegia, therapeutic KT may not provide improvements in the upper extremity function, daily activity, and quality of life over sham KT during conventional inpatient rehabilitation. CLINICAL REHABILITATION IMPACT: Kinesiology taping may provide positive effects on shoulder flexion and decrease the occurrence of HSP in subacute stroke patients with hemiplegic shoulders during conventional inpatient rehabilitation.

Exploring in vivo cholesterol-mediated interactions between activated EGF receptors in plasma membrane with single-molecule optical tracking.

BACKGROUND: The first step in many cellular signaling processes occurs at various types of receptors in the plasma membrane. Membrane cholesterol can alter these signaling pathways of living cells. However, the process in which the interaction of activated receptors is modulated by cholesterol remains unclear. METHODS: In this study, we measured single-molecule optical trajectories of epidermal growth factor receptors moving in the plasma membranes of two cancerous cell lines and one normal endothelial cell line. A stochastic model was developed and applied to identify critical information from single-molecule trajectories. RESULTS: We discovered that unliganded epidermal growth factor receptors may reside nearby cholesterol-riched regions of the plasma membrane and can move into these lipid domains when subjected to ligand binding. The amount of membrane cholesterol considerably affects the stability of correlated motion of activated epidermal growth factor receptors. CONCLUSIONS: Our results provide single-molecule evidence of membrane cholesterol in regulating signaling receptors. Because the three cell lines used for this study are quite diverse, our results may be useful to shed light on the mechanism of cholesterol-mediated interaction between activated receptors in live cells.

Repair of dentin defects from DSPP knockout mice by PILP mineralization.

Dentinogenesis imperfecta type II (DGI-II) lacks intrafibrillar mineral with severe compromise of dentin mechanical properties. A Dspp knockout (Dspp-/-) mouse, with a phenotype similar to that of human DGI-II, was used to determine if poly-L-aspartic acid [poly(ASP)] in the "polymer-induced liquid-precursor" (PILP) system can restore its mechanical properties. Dentin from six-week old Dspp-/- and wild-type mice was treated with CaP solution containing poly(ASP) for up to 14 days. Elastic modulus and hardness before and after treatment were correlated with mineralization from Micro x-ray computed tomography (Micro-XCT). Transmission electron microscopy (TEM)/Selected area electron diffraction (SAED) were used to compare matrix mineralization and crystallography. Mechanical properties of the Dspp-/- dentin were significantly less than wild-type dentin and recovered significantly (P < 0.05) after PILP-treatment, reaching values comparable to wild-type dentin. Micro-XCT showed mineral recovery similar to wild-type dentin after PILP-treatment. TEM/SAED showed repair of patchy mineralization and complete mineralization of defective dentin. This approach may lead to new strategies for hard tissue repair.

Deficits in executive functions among youths with autism spectrum disorders: an age-stratified analysis.

BACKGROUND: Impaired executive function (EF) is suggested to be one of the core features in individuals with autism spectrum disorders (ASD); however, little is known about whether the extent of worse EF in ASD than typically developing (TD) controls is age-dependent. We used age-stratified analysis to reveal this issue. METHOD: We assessed 111 youths with ASD (aged 12.5 ± 2.8 years, male 94.6%) and 114 age-, and sex-matched TD controls with Digit Span and four EF tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB): Spatial Span (SSP), Spatial Working Memory (SWM), Stockings of Cambridge (SOC), and Intradimensional/Extradimensional Shift Test (I/ED). RESULTS: Compared to TD controls, youths with ASD performed poorer on the Digit Span, SWM, SOC, and I/ED tasks. The performance of all the tasks improved with age for both groups. Age-stratified analyses were conducted due to significant age × group interactions in visuospatial planning (SOC) and set-shifting (I/ED) and showed that poorer performance on these two tasks in ASD than TD controls was found only in the child (aged 8-12 years) rather than the adolescent (aged 13-18 years) group. By contrast, youths with ASD had impaired working memory, regardless of age. The increased magnitude of group difference in visuospatial planning (SOC) with increased task demands differed between the two age groups but no age moderating effect on spatial working memory. CONCLUSIONS: Our findings support deficits in visuospatial working memory and planning in youths with ASD; however, worse performance in set-shifting may only be demonstrated in children with ASD.

Aberrant expression of microRNAs as biomarker for schizophrenia: from acute state to partial remission, and from peripheral blood to cortical tissue.

Based on our previous finding of a seven-miRNA (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) signature as a potential biomarker for schizophrenia, this study aimed to examine if hospitalization could affect expressions of these miRNAs. We compared their expression levels between acute state and partial remission state in people with schizophrenia (n=48) using quantitative PCR method. Further, to examine whether the blood and brain show similar expression patterns, the expressions of two miRNAs (hsa-miR-34a and hsa-miR-548d) were examined in the postmortem brain tissue of people with schizophrenia (n=25) and controls (n=27). The expression level of the seven miRNAs did not alter after ~2 months of hospitalization with significant improvement in clinical symptoms, suggesting the miRNAs could be traits rather than state-dependent markers. The aberrant expression seen in the blood of hsa-miR-34a and hsa-miR-548d were not present in the brain samples, but this does not discount the possibility that the peripheral miRNAs could be clinically useful biomarkers for schizophrenia. Unexpectedly, we found an age-dependent increase in hsa-miR-34a expressions in human cortical (Brodmann area 46 (BA46)) but not subcortical region (caudate putamen). The correlation between hsa-miR-34a expression level in BA46 and age was much stronger in the controls than in the cases, and the corresponding correlation in the blood was only seen in the cases. The association between the miRNA dysregulations, the disease predisposition and aging warrants further investigation. Taken together, this study provides further insight on the candidate peripheral miRNAs as stable biomarkers for the diagnostics of schizophrenia.

Distinct decalcification process of dentin by different cariogenic organic acids: Kinetics, ultrastructure and mechanical properties.

OBJECTIVES: We studied artificial dentin lesions in human teeth generated by lactate and acetate buffers (pH 5.0), the two most abundant acids in caries. The objective of this study was to determine differences in mechanical properties, mineral density profiles and ultrastructural variations of two different artificial lesions with the same approximate depth. METHODS: 0.05M (pH 5.0) acetate or lactate buffer was used to create 1) 180µm-deep lesions in non-carious human dentin blocks (acetate 130h; lactate 14days); (2) demineralized, ∼180µm-thick non-carious dentin discs (3 weeks). We performed nanoindentation to determine mechanical properties across the hydrated lesions, and micro X-ray computed tomography (MicroXCT) to determine mineral profiles. Ultrastructure in lesions was analyzed by TEM/selected area electron diffraction (SAED). Demineralized dentin discs were analyzed by small angle X-ray scattering (SAXS). RESULTS: Diffusion-dominated demineralization was shown based on the linearity between lesion depths versus the square root of exposure time in either solution, with faster kinetics in acetate buffer. Nanoindentation revealed lactate induced a significantly sharper transition in reduced elastic modulus across the lesions. MicroXCT showed lactate demineralized lesions had swelling and more disorganized matrix structure, whereas acetate lesions had abrupt X-ray absorption near the margin. At the ultrastructural level, TEM showed lactate was more effective in removing minerals from the collagenous matrix, which was confirmed by SAXS analysis. CONCLUSIONS: These findings indicated the different acids yielded lesions with different characteristics that could influence lesion formation resulting in their distinct predominance in different caries activities, and these differences may impact strategies for dentin caries remineralization.

Dietary resistant maltodextrin ameliorates testicular function and spermatogenesis in streptozotocin-nicotinamide-induced diabetic rats.

This study investigated the effect of resistant maltodextrin (RMD) on reproduction in streptozotocin (STZ)-nicotinamide-induced type 2 diabetic male rats. Forty male rats were induced with diabetes by a single intraperitoneal injection of STZ (50 mg kg(-1)) and nicotinamide (100 mg kg(-1)). Five groups were analysed in total: normal, diabetic rats without RMD, diabetic rats with RMD 1.2 g per 100 g diet (1×), with RMD 2.4 g per 100 g (2×), and with RMD 6.0 g per 100 g (5×). The groups of diabetic rats with the RMD supplement, compared to those without supplement, showed improved plasma glucose control, attenuated insulin resistance and recovery of testosterone level and spermatogenesis stage. The STZ-nicotinamide-induced diabetes mellitus (DM) caused a significant reduction in serum testosterone, testis androgen receptor (AR), steroidogenic acute regulatory protein (StAR) and 3ß-hydroxysteroid dehydrogenase (3ß-HSD) protein, but a statistical recovery in each of these was observed in the 5× group. TUNEL-positive cells were observed in the diabetic without RMD group, and RMD treatment reduced apoptotic germ cells. The expression of Bax/Bcl2 was induced in the diabetic group and also significantly reduced in the 5× group. Dietary RMD may improve metabolic control in STZ-nicotinamide-induced diabetic rats and attenuate hyperglycaemia-related impaired male reproduction and testicular function.

CO Emission from an Impinging Non-Premixed Flame.

Carbon monoxide (CO) results from the incomplete oxidation of hydrocarbon fuels. While CO can be desirable in some syngas processes, it is a dangerous emission from fires, gas heaters, gas stoves, or furnaces where insufficient oxygen in the core reaction prevents complete oxidation of fuel to carbon dioxide and water, particularly when the reaction is interrupted by interaction with relatively cool solid boundaries. This research examines the physico-thermo-chemical processes responsible for carbon monoxide release from a small laminar non-premixed methane/air flame impinging on a nearby surface. We measure the changes in CO emission as correlated with variations in flame structure observed using planar laser induced fluorescence (PLIF of OH and 2-photon CO), and two-line OH PLIF thermometry, as a function of burner-to-plate distance. In particular, this work combines the use of OH and CO PLIF, and PLIF thermometry to describe the relative locations of the CO rich region, the peak heat release zone as indicated by chemiluminescence and OH gradients, and the extended oxidative zone in the impinging flames. The results show that CO release correlates strongly with stagnating flow-driven changes in the location and extent of high concentration regions of OH in surface-impinging diffusion flames.