SERPINA11 related novel serpinopathy - A perinatal lethal disorder.

SERPINA11 is a hitherto poorly characterised gene belonging to Clade A of the SERPIN superfamily, with unknown expression pattern and functional significance. We report a perinatal lethal phenotype in two foetuses from the same family associated with a biallelic loss of function variant in SERPINA11, and provide functional evidence to support its candidature as a Mendelian disorder. The SERPINA11 variant-associated foetal phenotype is characterised by gross and histopathological features of extracellular matrix disruption. Western blot and immunofluorescence analyses revealed SERPINA11 expression in multiple mouse tissues, with pronounced expression in the bronchiolar epithelium. We observed a significant decrease in SERPINA11 immunofluorescence in the affected foetal lung compared with a healthy gestation-matched foetus. Protein expression data from HEK293T cell lines following site-directed mutagenesis support the loss of function nature of the variant. Transcriptome analysis from the affected foetal liver indicated the possibility of reduced SERPINA11 transcript abundance. This novel serpinopathy appears to be a consequence of the loss of inhibition of serine proteases involved in extracellular matrix remodelling, revealing SERPINA11 as a protease inhibitor critical for embryonic development.

Hierarchical Multicriteria Optimization of Molecular Models of Water.

Many widely used molecular models of water are built from a single Lennard-Jones site on which three point charges are positioned, one negative and two positive ones. Models from that class, denoted LJ3PC here, are computationally efficient, but it is well known that they cannot represent all relevant properties of water simultaneously with good accuracy. Despite the importance of the LJ3PC water model class, its inherent limitations in simultaneously describing different properties of water have never been studied systematically. This task can only be solved by multicriteria optimization (MCO). However, due to its computational cost, applying MCO to molecular models is a formidable task. We have recently introduced the reduced units method (RUM) to cope with this problem. In the present work, we apply the RUM in a hierarchical scheme to optimize LJ3PC water models taking into account five objectives: the representation of vapor pressure, saturated liquid density, self-diffusion coefficient, shear viscosity, and relative permittivity. Of the six parameters of the LJ3PC models, five were varied; only the H-O-H bond angle, which is usually chosen based on physical arguments, was kept constant. Our hierarchical RUM-based approach yields a Pareto set that contains attractive new water models. Furthermore, the results give an idea of what can be achieved by molecular modeling of water with models from the LJ3PC class.

Rapid characterization of adeno-associated virus (AAV) capsid proteins using microchip ZipChip CE-MS.

Adeno-associated viruses (AAVs) are viral vectors used as delivery systems for gene therapies. Intact protein characterization of AAV viral capsid proteins (VPs) and their post-translational modifications is critical to ensuring product quality. In this study, microchip-based ZipChip capillary electrophoresis-mass spectrometry (CE-MS) was applied for the rapid characterization of AAV intact VPs, specifically full and empty viral capsids of serotypes AAV6, AAV8 and AAV9, which was accomplished using 5 min of analysis time. Low levels of dimethyl sulfoxide (4%) in the background electrolyte (BGE) improved MS signal quality and component detection. A sensitivity evaluation revealed consistent detection of VP proteoforms when as little as 2.64 × 106 viral particles (≈26.4 picograms) were injected. Besides the traditional VP proteoforms used for serotype identification, multiple VP3 variants were detected, including truncated VP3 variants most likely generated by leaky scanning as well as unacetylated and un-cleaved VP3 proteoforms. Phosphorylation, known to impact AAV transduction efficiency, was also seen in all serotypes analysed. Additionally, low abundant fragments originating from either N- or C-terminus truncation were detected. As the aforementioned VP components can impact product quality and efficacy, the ZipChip's ability to rapidly characterize them illustrates its strength in monitoring product quality during AAV production.

Predictors of Emotional Prosody Identification by School-Age Children With Cochlear Implants and Their Peers With Normal Hearing.

OBJECTIVES: Children with cochlear implants (CIs) vary widely in their ability to identify emotions in speech. The causes of this variability are unknown, but this knowledge will be crucial if we are to design improvements in technological or rehabilitative interventions that are effective for individual patients. The objective of this study was to investigate how well factors such as age at implantation, duration of device experience (hearing age), nonverbal cognition, vocabulary, and socioeconomic status predict prosody-based emotion identification in children with CIs, and how the key predictors in this population compare to children with normal hearing who are listening to either normal emotional speech or to degraded speech. DESIGN: We measured vocal emotion identification in 47 school-age CI recipients aged 7 to 19 years in a single-interval, 5-alternative forced-choice task. None of the participants had usable residual hearing based on parent/caregiver report. Stimuli consisted of a set of semantically emotion-neutral sentences that were recorded by 4 talkers in child-directed and adult-directed prosody corresponding to five emotions: neutral, angry, happy, sad, and scared. Twenty-one children with normal hearing were also tested in the same tasks; they listened to both original speech and to versions that had been noise-vocoded to simulate CI information processing. RESULTS: Group comparison confirmed the expected deficit in CI participants' emotion identification relative to participants with normal hearing. Within the CI group, increasing hearing age (correlated with developmental age) and nonverbal cognition outcomes predicted emotion recognition scores. Stimulus-related factors such as talker and emotional category also influenced performance and were involved in interactions with hearing age and cognition. Age at implantation was not predictive of emotion identification. Unlike the CI participants, neither cognitive status nor vocabulary predicted outcomes in participants with normal hearing, whether listening to original speech or CI-simulated speech. Age-related improvements in outcomes were similar in the two groups. Participants with normal hearing listening to original speech showed the greatest differences in their scores for different talkers and emotions. Participants with normal hearing listening to CI-simulated speech showed significant deficits compared with their performance with original speech materials, and their scores also showed the least effect of talker- and emotion-based variability. CI participants showed more variation in their scores with different talkers and emotions than participants with normal hearing listening to CI-simulated speech, but less so than participants with normal hearing listening to original speech. CONCLUSIONS: Taken together, these results confirm previous findings that pediatric CI recipients have deficits in emotion identification based on prosodic cues, but they improve with age and experience at a rate that is similar to peers with normal hearing. Unlike participants with normal hearing, nonverbal cognition played a significant role in CI listeners' emotion identification. Specifically, nonverbal cognition predicted the extent to which individual CI users could benefit from some talkers being more expressive of emotions than others, and this effect was greater in CI users who had less experience with their device (or were younger) than CI users who had more experience with their device (or were older). Thus, in young prelingually deaf children with CIs performing an emotional prosody identification task, cognitive resources may be harnessed to a greater degree than in older prelingually deaf children with CIs or than children with normal hearing.

Fetal presentation of chondrodysplasia with joint dislocations, GPAPP type, caused by novel biallelic IMPAD1 variants.

Biallelic IMPAD1 pathogenic variants leads to deficiency of GPAPP (Golgi 3-prime phosphoadenosine 5-prime phosphate 3-prime phosphatase) protein and clinically causes chondrodysplasia, which is characterized by short stature with short limbs, craniofacial malformations, cleft palate, hand and foot anomalies, and various radiographic skeletal manifestations. Here we describe prenatal presentation of GPAPP deficiency caused by novel biallelic pathogenic variants, 2 base pair duplication in exon 2 of IMAPD1 gene in a patient of Asian-Indian origin. Further we report on diagnostic clues of prenatal presentation of GPAPP deficiency through ultrasonography, fetal MRI, and postmortem findings. We also provide evidence of pathophysiology of underlying GPAPP deficiency in the form of disorganization and dysplastic chondrocytes and reduced sulfation of glycoproteins through histopathology of cartilage similar to that described in mice IMPAD1 homozygous mutant model.

Design, synthesis and biological evaluation studies of novel small molecule ENPP1 inhibitors for cancer immunotherapy.

Ecto-nucleotide pyrophosphatase/phosphodiesterases 1 (ENPP1 or NPP1), is an attractive therapeutic target for various diseases, primarily cancer and mineralization disorders. The ecto-enzyme is located on the cell surface and has been implicated in the control of extracellular levels of nucleotide, nucleoside and (di) phosphate. Recently, it has emerged as a critical phosphodiesterase that hydrolyzes cyclic 2'3'- cGAMP, the endogenous ligand for STING (STimulator of INterferon Genes). STING plays an important role in innate immunity by activating type I interferon in response to cytosolic 2'3'-cGAMP. ENPP1 negatively regulates the STING pathway and hence its inhibition makes it an attractive therapeutic target for cancer immunotherapy. Herein, we describe the design, optimization and biological evaluation studies of a series of novel non-nucleotidic thioguanine based small molecule inhibitors of ENPP1. The lead compound 43 has shown good in vitro potency, stability in SGF/SIF/PBS, selectivity, ADME properties and pharmacokinetic profile and finally potent anti-tumor response in vivo. These compounds are a good starting point for the development of potentially effective cancer immunotherapy agents.

Fetal phenotypes of Mendelian disorders: A descriptive study from India.

OBJECTIVE: Exome sequencing (ES)-based diagnosis of Mendelian diseases in the fetus is limited by paucity of phenotypic information. This study reports the comprehensive phenotypes of some fetuses with Mendelian disorders. METHODS: Next generation technology-based sequencing of all coding regions of the genome (Exome sequencing) or targeted gene sequencing using Sanger or next generation platforms was performed in a cohort of deeply phenotyped, cytogenetically normal fetuses with morphological defects. Prenatal ultrasonographic phenotypes and postmortem details including dysmorphology, histopathology, and radiography were ascertained. Novel candidate genes, novel/unusual findings, and unusual genotypes in cases with confirmed Mendelian disorders are described. RESULTS: Of the 102 fetuses sequenced, 45 (44%) achieved definitive diagnosis of a Mendelian disorder with 50 pathogenic/likely pathogenic variants. The majority (87%) were autosomal recessive, 69% families were consanguineous, and 54% variants were novel. Dysmorphic syndromes, skeletal dysplasias, and metabolic disorders were the commonest disease categories, ciliopathies and dystroglycanopathies, commonest molecular categories. We describe the first fetal description of six monogenic diseases, and nine cases with novel histological findings. Nineteen cases had novel/unusual findings. CONCLUSION: This cohort demonstrates how deep fetal phenotypes of some Mendelian disorders can show novel/unusual findings, which have important implications for prenatal diagnosis of these conditions.

Umbilical port versus epigastric port for gallbladder extraction in laparoscopic cholecystectomy: A systematic review and meta-analysis of randomized controlled trials with trial sequential analysis.

BACKGROUND: After laparoscopic cholecystectomy, gallbladder can be extracted either from epigastric/subxiphoid port or umbilical port. We conducted systematic review of randomized controlled trials comparing the two. METHODS: PRISMA-compliant systematic review and meta-analysis was conducted with pre-specified study protocol registered on PROSPERO (CRD42019128662). Multiple databases were searched from inception till 14 September 2019 using search terms "gallbladder", "specimen", "extraction', "extract", "cholecystectomy", "epigastric port", "subxiphoid port" "umbilical port". Outcomes assessed were postoperative pain (visual analog scale at 24 h postoperatively), port-site hernia, port-site infection, operative time and gallbladder retrieval time. Data were analyzed using random-effects models with risk ratios (RR) for dichotomous variables and mean difference (MD) for continuous variables. RESULTS: Of 280 articles retrieved, 9 RCT's with 1036 participants were included. Quality of included studies was judged to be "moderate" to "low". There was no difference in postoperative pain at 24 h (p = 0.76), total operative time (p = 0.11), gallbladder retrieval time (p = 0.72) or surgical site infection (p = 0.93). Umbilical port retrieval was associated with significantly higher risk of port-site herniae (RR 2.68, 95%CI:1.06-6.80, p = 0.04). After sensitivity analysis, operative time was significantly shorter with epigastric retrieval (p = 0.0007). Trial sequential analysis showed that current studies were successful in achieving optimum information size for primary outcome. CONCLUSIONS: There was no difference in postoperative pain and infections between umbilical and epigastric port retrieval. Umbilical port retrieval was associated with significantly higher risk of developing port-site hernia and could also be associated with longer operative time. Epigastric port may be favorable for gallbladder retrieval in multiport laparoscopic cholecystectomy.

AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model.

Cyclic GMP-AMP synthase (cGAS) is an endogenous DNA sensor that synthesizes cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) from ATP and GTP. 2'3'-cGAMP activates the stimulator of interferon genes (STING) pathway, resulting in the production of interferons and pro-inflammatory cytokines. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the phosphodiesterase that negatively regulates the STING pathway by hydrolyzing 2'3'-cGAMP. It has been established that the cGAS-STING pathway plays a major role in inhibiting tumor growth by upregulating T cell response. Herein, we demonstrate that AVA-NP-695, a selective and highly potent ENPP1 inhibitor, apart from the immunomodulatory effect also modulates cancer metastasis by negatively regulating epithelial-mesenchymal transition (EMT). We established that the combined addition of 2'3'-cGAMP and AVA-NP-695 significantly abrogated the transforming growth factor beta (TGF-ꞵ)-induced EMT in MDA-MB-231 cells. Finally, results from the in vivo study showed superior tumor growth inhibition and impact on tumor metastasis of AVA-NP-695 compared to Olaparib and PD-1 in a syngeneic 4T1 breast cancer mouse model. The translation of efficacy from in vitro to in vivo 4T1 tumor model provides a strong rationale for the therapeutic potential of AVA-NP-695 against triple-negative breast cancer (TNBC) as an immunomodulatory and anti-metastatic agent.

A machine learning-based gene signature of response to the novel alkylating agent LP-184 distinguishes its potential tumor indications.

BACKGROUND: Non-targeted cytotoxics with anticancer activity are often developed through preclinical stages using response criteria observed in cell lines and xenografts. A panel of the NCI-60 cell lines is frequently the first line to define tumor types that are optimally responsive. Open data on the gene expression of the NCI-60 cell lines, provides a unique opportunity to add another dimension to the preclinical development of such drugs by interrogating correlations with gene expression patterns. Machine learning can be used to reduce the complexity of whole genome gene expression patterns to derive manageable signatures of response. Application of machine learning in early phases of preclinical development is likely to allow a better positioning and ultimate clinical success of molecules. LP-184 is a highly potent novel alkylating agent where the preclinical development is being guided by a dedicated machine learning-derived response signature. We show the feasibility and the accuracy of such a signature of response by accurately predicting the response to LP-184 validated using wet lab derived IC50s on a panel of cell lines. RESULTS: We applied our proprietary RADR® platform to an NCI-60 discovery dataset encompassing LP-184 IC50s and publicly available gene expression data. We used multiple feature selection layers followed by the XGBoost regression model and reduced the complexity of 20,000 gene expression values to generate a 16-gene signature leading to the identification of a set of predictive candidate biomarkers which form an LP-184 response gene signature. We further validated this signature and predicted response to an additional panel of cell lines. Considering fold change differences and correlation between actual and predicted LP-184 IC50 values as validation performance measures, we obtained 86% accuracy at four-fold cut-off, and a strong (r = 0.70) and significant (p value 1.36e-06) correlation between actual and predicted LP-184 sensitivity. In agreement with the perceived mechanism of action of LP-184, PTGR1 emerged as the top weighted gene. CONCLUSION: Integration of a machine learning-derived signature of response with in vitro assessment of LP-184 efficacy facilitated the derivation of manageable yet robust biomarkers which can be used to predict drug sensitivity with high accuracy and clinical value.

Solid-State Isolation of Cyclic Alkyl(Amino) Carbene (cAAC)-Supported Structurally Diverse Alkali Metal-Phosphinidenides.

Cyclic alkyl(amino) carbene (cAAC)-supported, structurally diverse alkali metal-phosphinidenides 2-5 of general formula ((cAAC)P-M)n (THF)x [2: M=K, n=2, x=4; 3: M=K, n=6, x=2; 4: M=K, n=4, x=4; 5: M=Na, n=3, x=1] have been synthesized by the reduction of cAAC-stabilized chloro-phosphinidene cAAC=P-Cl (1) utilizing metallic K or KC8 and Na-naphthalenide as reducing agents. Complexes 2-5 have been structurally characterized in solid state by NMR studies and single crystal X-ray diffraction. The proposed mechanism for the electron transfer process has been well-supported by cyclic voltammetry (CV) studies and Density Functional Theory (DFT) calculations. The solid state oligomerization process has been observed to be largely dependent on the ionic radii of alkali metal ions, steric bulk of cAAC ligands and solvation/de-solvation/recombination of the dimeric unit [(cAAC)P-M(THF)x ]2 .

Identification and structure-activity relationship studies of small molecule inhibitors of the human cathepsin D.

Cathepsin D, an aspartyl protease, is an attractive therapeutic target for various diseases, primarily cancer and osteoarthritis. However, despite several small molecule cathepsin D inhibitors being developed, that are highly potent, most of them show poor microsomal stability, which in turn limits their clinical translation. Herein, we describe the design, optimization and evaluation of a series of novel non-peptidic acylguanidine based small molecule inhibitors of cathepsin D. Optimization of our hit compound 1a (IC50 = 29 nM) led to the highly potent mono sulphonamide analogue 4b (IC50 = 4 nM), however with poor microsomal stability (HLM: 177 and MLM: 177 µl/min/mg). To further improve the microsomal stability while retaining the potency, we carried out an extensive structure-activity relationship screen which led to the identification of our optimised lead 24e (IC50 = 45 nM), with an improved microsomal stability (HLM: 59.1 and MLM: 86.8 µl/min/mg). Our efforts reveal that 24e could be a good starting point or potential candidate for further preclinical studies against diseases where Cathepsin D plays an important role.

Perception of Child-Directed Versus Adult-Directed Emotional Speech in Pediatric Cochlear Implant Users.

OBJECTIVES: Cochlear implants (CIs) are remarkable in allowing individuals with severe to profound hearing loss to perceive speech. Despite these gains in speech understanding, however, CI users often struggle to perceive elements such as vocal emotion and prosody, as CIs are unable to transmit the spectro-temporal detail needed to decode affective cues. This issue becomes particularly important for children with CIs, but little is known about their emotional development. In a previous study, pediatric CI users showed deficits in voice emotion recognition with child-directed stimuli featuring exaggerated prosody. However, the large intersubject variability and differential developmental trajectory known in this population incited us to question the extent to which exaggerated prosody would facilitate performance in this task. Thus, the authors revisited the question with both adult-directed and child-directed stimuli. DESIGN: Vocal emotion recognition was measured using both child-directed (CDS) and adult-directed (ADS) speech conditions. Pediatric CI users, aged 7-19 years old, with no cognitive or visual impairments and who communicated through oral communication with English as the primary language participated in the experiment (n = 27). Stimuli comprised 12 sentences selected from the HINT database. The sentences were spoken by male and female talkers in a CDS or ADS manner, in each of the five target emotions (happy, sad, neutral, scared, and angry). The chosen sentences were semantically emotion-neutral. Percent correct emotion recognition scores were analyzed for each participant in each condition (CDS vs. ADS). Children also completed cognitive tests of nonverbal IQ and receptive vocabulary, while parents completed questionnaires of CI and hearing history. It was predicted that the reduced prosodic variations found in the ADS condition would result in lower vocal emotion recognition scores compared with the CDS condition. Moreover, it was hypothesized that cognitive factors, perceptual sensitivity to complex pitch changes, and elements of each child's hearing history may serve as predictors of performance on vocal emotion recognition. RESULTS: Consistent with our hypothesis, pediatric CI users scored higher on CDS compared with ADS speech stimuli, suggesting that speaking with an exaggerated prosody-akin to "motherese"-may be a viable way to convey emotional content. Significant talker effects were also observed in that higher scores were found for the female talker for both conditions. Multiple regression analysis showed that nonverbal IQ was a significant predictor of CDS emotion recognition scores while Years using CI was a significant predictor of ADS scores. Confusion matrix analyses revealed a dependence of results on specific emotions; for the CDS condition's female talker, participants had high sensitivity (d' scores) to happy and low sensitivity to the neutral sentences while for the ADS condition, low sensitivity was found for the scared sentences. CONCLUSIONS: In general, participants had higher vocal emotion recognition to the CDS condition which also had more variability in pitch and intensity and thus more exaggerated prosody, in comparison to the ADS condition. Results suggest that pediatric CI users struggle with vocal emotion perception in general, particularly to adult-directed speech. The authors believe these results have broad implications for understanding how CI users perceive emotions both from an auditory communication standpoint and a socio-developmental perspective.

Exome sequencing for perinatal phenotypes: The significance of deep phenotyping.

OBJECTIVE: To ascertain the performance of exome sequencing (ES) technology for determining the etiological basis of abnormal perinatal phenotypes and to study the impact of comprehensive phenotyping on variant prioritization. METHODS: A carefully selected cohort of 32/204 fetuses with abnormal perinatal phenotypes following postmortem/postnatal deep phenotyping underwent ES to identify a causative variant for the fetal phenotype. A retrospective comparative analysis of the prenatal versus postmortem/postnatal phenotype-based variant prioritization was performed with aid of Phenolyzer software. A review of selected literature reports was done to examine the completeness of phenotypic information for cases in those reports and how it impacted the performance of fetal ES. RESULTS: In 18/32 (56%) fetuses, a pathogenic/likely pathogenic variant was identified. This included novel genotype-phenotype associations, expanded prenatal phenotypes of known Mendelian disorders and dual Mendelian diagnoses. The retrospective analysis revealed that the putative diagnostic variant could not be identified on basis of prenatal findings alone in 15/22 (68%) cases, indicating the importance of comprehensive postmortem/postnatal phenotype information. Literature review was supportive of these findings but could not be conclusive due to marked heterogeneity of involved studies. CONCLUSION: Comprehensive phenotyping is essential for improving diagnostic performance and facilitating identification of novel genotype-phenotype associations in perinatal cohorts undergoing ES.

Effects of Age and Hearing Loss on the Recognition of Emotions in Speech.

OBJECTIVES: Emotional communication is a cornerstone of social cognition and informs human interaction. Previous studies have shown deficits in facial and vocal emotion recognition in older adults, particularly for negative emotions. However, few studies have examined combined effects of aging and hearing loss on vocal emotion recognition by adults. The objective of this study was to compare vocal emotion recognition in adults with hearing loss relative to age-matched peers with normal hearing. We hypothesized that age would play a role in emotion recognition and that listeners with hearing loss would show deficits across the age range. DESIGN: Thirty-two adults (22 to 74 years of age) with mild to severe, symmetrical sensorineural hearing loss, amplified with bilateral hearing aids and 30 adults (21 to 75 years of age) with normal hearing, participated in the study. Stimuli consisted of sentences spoken by 2 talkers, 1 male, 1 female, in 5 emotions (angry, happy, neutral, sad, and scared) in an adult-directed manner. The task involved a single-interval, five-alternative forced-choice paradigm, in which the participants listened to individual sentences and indicated which of the five emotions was targeted in each sentence. Reaction time was recorded as an indirect measure of cognitive load. RESULTS: Results showed significant effects of age. Older listeners had reduced accuracy, increased reaction times, and reduced d' values. Normal hearing listeners showed an Age by Talker interaction where older listeners had more difficulty identifying male vocal emotion. Listeners with hearing loss showed reduced accuracy, increased reaction times, and lower d' values compared with age-matched normal-hearing listeners. Within the group with hearing loss, age and talker effects were significant, and low-frequency pure-tone averages showed a marginally significant effect. Contrary to other studies, once hearing thresholds were taken into account, no effects of listener sex were observed, nor were there effects of individual emotions on accuracy. However, reaction times and d' values showed significant differences between individual emotions. CONCLUSIONS: The results of this study confirm existing findings in the literature showing that older adults show significant deficits in voice emotion recognition compared with their normally hearing peers, and that among listeners with normal hearing, age-related changes in hearing do not predict this age-related deficit. The present results also add to the literature by showing that hearing impairment contributes additionally to deficits in vocal emotion recognition, separate from deficits related to age. These effects of age and hearing loss appear to be quite robust, being evident in reduced accuracy scores and d' measures, as well as in reaction time measures.

Children's Recognition of Emotional Prosody in Spectrally Degraded Speech Is Predicted by Their Age and Cognitive Status.

OBJECTIVES: It is known that school-aged children with cochlear implants show deficits in voice emotion recognition relative to normal-hearing peers. Little, however, is known about normal-hearing children's processing of emotional cues in cochlear implant-simulated, spectrally degraded speech. The objective of this study was to investigate school-aged, normal-hearing children's recognition of voice emotion, and the degree to which their performance could be predicted by their age, vocabulary, and cognitive factors such as nonverbal intelligence and executive function. DESIGN: Normal-hearing children (6-19 years old) and young adults were tested on a voice emotion recognition task under three different conditions of spectral degradation using cochlear implant simulations (full-spectrum, 16-channel, and 8-channel noise-vocoded speech). Measures of vocabulary, nonverbal intelligence, and executive function were obtained as well. RESULTS: Adults outperformed children on all tasks, and a strong developmental effect was observed. The children's age, the degree of spectral resolution, and nonverbal intelligence were predictors of performance, but vocabulary and executive functions were not, and no interactions were observed between age and spectral resolution. CONCLUSIONS: These results indicate that cognitive function and age play important roles in children's ability to process emotional prosody in spectrally degraded speech. The lack of an interaction between the degree of spectral resolution and children's age further suggests that younger and older children may benefit similarly from improvements in spectral resolution. The findings imply that younger and older children with cochlear implants may benefit similarly from technical advances that improve spectral resolution.

Modulation detection interference in cochlear implant listeners under forward masking conditions.

Little is known about cochlear implant (CI) users' ability to process amplitude modulation (AM) under conditions of forward masking (forward-modulation detection/discrimination interference, or F-MDI). In this study, F-MDI was investigated in adult CI listeners using direct electrical stimulation via research interface. The target was sinusoidally amplitude modulated at 50 Hz, and presented to a fixed electrode in the middle of the array. The forward masker was either amplitude modulated at the same rate (AM) or unmodulated and presented at the peak amplitude of its AM counterpart (steady-state peak, SSP). Results showed that the AM masker produced higher modulation thresholds in the target than the SSP masker. The difference (F-MDI) was estimated to be 4.6 dB on average, and did not change with masker-target delays up to 100 ms or with masker-target spatial electrode distances up to eight electrodes. Results with a coherent remote cue presented with the masker showed that confusion effects did not play a role in the observed F-MDI. Traditional recovery from forward masking using the same maskers and a 20-ms probe, measured in four of the subjects, confirmed the expected result: higher thresholds with the SSP masker than the AM masker. Collectively, the results indicate that significant F-MDI occurs in CI users.

Synthesis and application of ß-carbolines as novel multi-functional anti-Alzheimer's disease agents.

The design, synthesis and assessment of ß-carboline core-based compounds as potential multifunctional agents against several processes that are believed to play a significant role in Alzheimer's disease (AD) pathology, are described. The activity of the compounds was determined in Aß self-assembly (fibril and oligomer formation) and cholinesterase (AChE, BuChE) activity inhibition, and their antioxidant properties were also assessed. To obtain insight into the mode of action of the compounds, HR-MS studies were carried out on the inhibitor-Aß complex formation and molecular docking was performed on inhibitor-BuChE interactions. While several compounds exhibited strong activities in individual assays, compound 14 emerged as a promising multi-target lead for the further structure-activity relationship studies.

Recovery from forward masking in cochlear implant listeners depends on stimulation mode, level, and electrode location.

Psychophysical recovery from forward masking was measured in adult cochlear implant users of CochlearTM and Advanced BionicsTM devices, in monopolar and in focused (bipolar and tripolar) stimulation modes, at four electrode sites across the arrays, and at two levels (loudness balanced across modes and electrodes). Results indicated a steeper psychophysical recovery from forward masking in monopolar over bipolar and tripolar modes, modified by differential effects of electrode and level. The interactions between factors varied somewhat across devices. It is speculated that psychophysical recovery from forward masking may be driven by different populations of neurons in the different modes, with a broader stimulation pattern resulting in a greater likelihood of response by healthier and/or faster-recovering neurons within the stimulated population. If a more rapid recovery from prior stimulation reflects responses of neurons not necessarily close to the activating site, the spectral pattern of the incoming acoustic signal may be distorted. These results have implications for speech processor implementations using different degrees of focusing of the electric field. The primary differences in the shape of the recovery function were observed in the earlier portion (between 2 and 45 ms) of recovery, which is significant in terms of the speech envelope.

A dynamin homolog promotes the transition from hemifusion to content mixing in intracellular membrane fusion.

The convergence of the antagonistic reactions of membrane fusion and fission at the hemifusion/hemifission intermediate has generated a captivating enigma of whether Soluble N-ethylmaleimide sensitive factor Attachment Protein Receptor (SNAREs) and dynamin have unusual counter-functions in fission and fusion, respectively. SNARE-mediated fusion and dynamin-driven fission are fundamental membrane flux reactions known to occur during ubiquitous cellular communication events such as exocytosis, endocytosis and vesicle transport. Here we demonstrate the influence of the dynamin homolog Vps1 (Vacuolar protein sorting 1) on lipid mixing and content mixing properties of yeast vacuoles, and on the incorporation of SNAREs into fusogenic complexes. We propose a novel concept that Vps1, through its oligomerization and SNARE domain binding, promotes the hemifusion-content mixing transition in yeast vacuole fusion by increasing the number of trans-SNAREs.