Automated analysis and detection of epileptic seizures in video recordings using artificial intelligence.

Introduction: Automated seizure detection promises to aid in the prevention of SUDEP and improve the quality of care by assisting in epilepsy diagnosis and treatment adjustment. Methods: In this phase 2 exploratory study, the performance of a contactless, marker-free, video-based motor seizure detection system is assessed, considering video recordings of patients (age 0-80 years), in terms of sensitivity, specificity, and Receiver Operating Characteristic (ROC) curves, with respect to video-electroencephalographic monitoring (VEM) as the medical gold standard. Detection performances of five categories of motor epileptic seizures (tonic-clonic, hyperkinetic, tonic, unclassified motor, automatisms) and psychogenic non-epileptic seizures (PNES) with a motor behavioral component lasting for >10 s were assessed independently at different detection thresholds (rather than as a categorical classification problem). A total of 230 patients were recruited in the study, of which 334 in-scope (>10 s) motor seizures (out of 1,114 total seizures) were identified by VEM reported from 81 patients. We analyzed both daytime and nocturnal recordings. The control threshold was evaluated at a range of values to compare the sensitivity (n = 81 subjects with seizures) and false detection rate (FDR) (n = all 230 subjects). Results: At optimal thresholds, the performance of seizure groups in terms of sensitivity (CI) and FDR/h (CI): tonic-clonic- 95.2% (82.4, 100%); 0.09 (0.077, 0.103), hyperkinetic- 92.9% (68.5, 98.7%); 0.64 (0.59, 0.69), tonic- 78.3% (64.4, 87.7%); 5.87 (5.51, 6.23), automatism- 86.7% (73.5, 97.7%); 3.34 (3.12, 3.58), unclassified motor seizures- 78% (65.4, 90.4%); 4.81 (4.50, 5.14), and PNES- 97.7% (97.7, 100%); 1.73 (1.61, 1.86). A generic threshold recommended for all motor seizures under study asserted 88% sensitivity and 6.48 FDR/h. Discussion: These results indicate an achievable performance for major motor seizure detection that is clinically applicable for use as a seizure screening solution in diagnostic workflows.

Neurodevelopmental disorders associated variants in ADAT3 disrupt the activity of the ADAT2/ADAT3 tRNA deaminase complex and impair neuronal migration.

The ADAT2/ADAT3 complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3 , the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders (NDDs). Yet, the physiological function of ADAT2/ADAT3 complex during brain development remains totally unknown. Here we showed that maintaining a proper level of ADAT2/ADAT3 catalytic activity is required for correct radial migration of projection neurons in the developing mouse cortex. In addition, we not only reported 7 new NDD patients carrying biallelic variants in ADAT3 but also deeply characterize the impact of those variants on ADAT2/ADAT3 structure, biochemical properties, enzymatic activity and tRNAs editing and abundance. We demonstrated that all the identified variants alter both the expression and the activity of the complex leading to a significant decrease of I 34 with direct consequence on their steady-state. Using in vivo complementation assays, we correlated the severity of the migration phenotype with the degree of the loss of function caused by the variants. Altogether, our results indicate a critical role of ADAT2/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenicity of ADAT3-related neurodevelopmental disorder.

Automatic classification of hyperkinetic, tonic, and tonic-clonic seizures using unsupervised clustering of video signals.

Introduction: This study evaluated the accuracy of motion signals extracted from video monitoring data to differentiate epileptic motor seizures in patients with drug-resistant epilepsy. 3D near-infrared video was recorded by the Nelli® seizure monitoring system (Tampere, Finland). Methods: 10 patients with 130 seizures were included in the training dataset, and 17 different patients with 98 seizures formed the testing dataset. Only seizures with unequivocal hyperkinetic, tonic, and tonic-clonic semiology were included. Motion features from the catch22 feature collection extracted from video were explored to transform the patients' videos into numerical time series for clustering and visualization. Results: Changes in feature generation provided incremental discrimination power to differentiate between hyperkinetic, tonic, and tonic-clonic seizures. Temporal motion features showed the best results in the unsupervised clustering analysis. Using these features, the system differentiated hyperkinetic, tonic and tonic-clonic seizures with 91, 88, and 45% accuracy after 100 cross-validation runs, respectively. F1-scores were 93, 90, and 37%, respectively. Overall accuracy and f1-score were 74%. Conclusion: The selected features of motion distinguished semiological differences within epileptic seizure types, enabling seizure classification to distinct motor seizure types. Further studies are needed with a larger dataset and additional seizure types. These results indicate the potential of video-based hybrid seizure monitoring systems to facilitate seizure classification improving the algorithmic processing and thus streamlining the clinical workflow for human annotators in hybrid (algorithmic-human) seizure monitoring systems.

An Experimental Method for Bio-Signal Denoising Using Unconventional Sensors.

In bio-signal denoising, current methods reported in the literature consider purely simulated environments, requiring high computational powers and signal processing algorithms that may introduce signal distortion. To achieve an efficient noise reduction, such methods require previous knowledge of the noise signals or to have certain periodicity and stability, making the noise estimation difficult to predict. In this paper, we solve these challenges through the development of an experimental method applied to bio-signal denoising using a combined approach. This is based on the implementation of unconventional electric field sensors used for creating a noise replica required to obtain the ideal Wiener filter transfer function and achieve further noise reduction. This work aims to investigate the suitability of the proposed approach for real-time noise reduction affecting bio-signal recordings. The experimental evaluation presented here considers two scenarios: (a) human bio-signals trials including electrocardiogram, electromyogram and electrooculogram; and (b) bio-signal recordings from the MIT-MIH arrhythmia database. The performance of the proposed method is evaluated using qualitative criteria (i.e., power spectral density) and quantitative criteria (i.e., signal-to-noise ratio and mean square error) followed by a comparison between the proposed methodology and state of the art denoising methods. The results indicate that the combined approach proposed in this paper can be used for noise reduction in electrocardiogram, electromyogram and electrooculogram signals, achieving noise attenuation levels of 26.4 dB, 21.2 dB and 40.8 dB, respectively.

A collection of novel Lotus japonicus LORE1 mutants perturbed in the nodulation program induced by the Agrobacterium pusense strain IRBG74.

The Lotus japonicus population carrying new Lotus retrotransposon 1 (LORE1) insertions represents a valuable biological resource for genetic research. New insertions were generated by activation of the endogenous retroelement LORE1a in the germline of the G329-3 plant line and arranged in a 2-D system for reverse genetics. LORE1 mutants identified in this collection contributes substantially to characterize candidate genes involved in symbiotic association of L. japonicus with its cognate symbiont, the nitrogen-fixing bacteria Mesorhizobium loti that infects root nodules intracellularly. In this study we aimed to identify novel players in the poorly explored intercellular infection induced by Agrobacterium pusense IRBG74 sp. For this purpose, a forward screen of > 200,000 LORE1 seedlings, obtained from bulk propagation of G329-3 plants, inoculated with IRBG74 was performed. Plants with perturbed nodulation were scored and the offspring were further tested on plates to confirm the symbiotic phenotype. A total of 110 Lotus mutants with impaired nodulation after inoculation with IRBG74 were obtained. A comparative analysis of nodulation kinetics in a subset of 20 mutants showed that most of the lines were predominantly affected in nodulation by IRBG74. Interestingly, additional defects in the main root growth were observed in some mutant lines. Sequencing of LORE1 flanking regions in 47 mutants revealed that 92 Lotus genes were disrupted by novel LORE1 insertions in these lines. In the IM-S34 mutant, one of the insertions was located in the 5´UTR of the LotjaGi5g1v0179800 gene, which encodes the AUTOPHAGY9 protein. Additional mutant alleles, named atg9-2 and atg9-3, were obtained in the reverse genetic collection. Nodule formation was significantly reduced in these mutant alleles after M. loti and IRBG74 inoculation, confirming the effectiveness of the mutant screening. This study describes an effective forward genetic approach to obtain novel mutants in Lotus with a phenotype of interest and to identify the causative gene(s).

Seroprevalencia y factores de riesgo asociados a toxoplasmosis gestacional en el Nororiente Colombiano / Seroprevalence and risk factors for congenital toxoplasmosis in the northeastern region of Colombia / Soroprevalência e fatores de risco associados à toxoplasmose gestacional no nordeste da Colômbia

Introduction: Toxoplasmosis is a zoonosis prevalent in one-third of the world's population, adversely affecting maternal-fetal health by causing varying degrees of damage to the fetus. Objective: To assess the seroprevalence of Toxoplasma gondii IgG and IgM antibodies and associated risk factors in first-trimester pregnant women in Cúcuta, Colombia, in 2018. Materials and Methods: Cross-sectional and correlational study in 111 women who voluntarily participated. Specific IgM and IgG antibodies were detected by luminescence immunoassay (LIA). Results: Total seropositivity for IgM and IgG was 19.8% and 35.1%, respectively, 11.7% was for IgM only, and 53.2% corresponded to the overall seronegativity rate for T. gondii. Risk factors (CI = 95%) such as undercooked meat consumption (54.1% of cases, OR = 1.8, p = 0.120), tap water consumption (48.6%, OR = 1.4, p = 0.421), and goat or cow raw milk consumption (39.6%, OR = 0.78, p = 0.553) were identified; in addition, living with cats (23.4%) was identified as a risk factor significantly associated with parasite seropositivity (OR = 2.8, p = 0.025). Discussion and Conclusions: Our findings showed a possible risk of primary infection in more than half of the pregnant population, given the seronegativity against the parasite. A considerable frequency of suspected cases of very recent infection was also found. In addition to being associated with a previously recognized risk factor, this fact suggests the presence of other dietary risks that should be addressed through prevention strategies during prenatal care and the need to strengthen event surveillance.

Introdução: A toxoplasmose é uma zoonose prevalente em um terço da população mundial, que afeta negativamente a saúde materno-fetal, causando diversos graus de danos ao feto. Objetivo: Propôs-se avaliar o estado sorológico IgG e IgM anti - Toxoplasma gondii e fatores de risco relacionados, em gestantes no primeiro trimestre em Cúcuta, Colômbia, no ano de 2018. Material e Métodos: Estudo transversal e correlacional em Participaram 111 mulheres voluntariamente, que foram testadas para IgM e IgG específicos pelo imunoensaio LIA. Resultados: 19,8% e 35,1% do total de soropositividade foram encontrados para IgM e IgG, respectivamente, 11,7% foi apenas para IgM e 53,2% corresponde à frequência de soronegatividade geral para T.gondii; Foram identificados fatores de risco (IC=95%) , como consumo de carne mal cozida (54,1% dos casos, OR= 1,8, p=0,120 ), água da torneira (48,6%, OR=1,4, p=0,421), cru leite de cabra ou vaca (39,6%, OR=0,78, p=0,553 ), além de conviver com gatos (23,4%), sendo este último significativamente associado à soropositividade ao parasita ( OR=2,8 , p =0,025 ). Discussão e conclusões: Nossos achados revelam um possível risco de infecção primária em mais da metade da população gestante dada a sua soronegatividade contra o parasita, mas também uma frequência considerável de casos com suspeita de infecção muito recente, que, além de estar associada a um fator de risco previamente reconhecido , sugere outros aspectos de risco em torno da alimentação que devem ser impactados por meio de estratégias de prevenção durante o pré-natal, sugerindo a necessidade de fortalecer a vigilância em torno do evento.

Non-invasive sensor methods used in monitoring newborn babies after birth, a clinical perspective.

BACKGROUND: Reducing the global new-born mortality is a paramount challenge for humanity. There are approximately 786,323 live births in the UK each year according to the office for National Statistics; around 10% of these newborn infants require assistance during this transition after birth. Each year around, globally around 2.5 million newborns die within their first month. The main causes are complications due to prematurity and during delivery. To act in a timely manner and prevent further damage, health professionals should rely on accurate monitoring of the main vital signs heart rate and respiratory rate. AIMS: To present a clinical perspective on innovative, non-invasive methods to monitor heart rate and respiratory rate in babies highlighting their advantages and limitations in comparison with well-established methods. METHODS: Using the data collected in our recently published systematic review we highlight the barriers and facilitators for the novel sensor devices in obtaining reliable heart rate measurements. Details about difficulties related to the application of sensors and interfaces, time to display, and user feedback are explored. We also provide a unique overview of using a non-invasive respiratory rate monitoring method by extracting RR from the pulse oximetry trace of newborn babies. RESULTS: Novel sensors to monitor heart rate offer the advantages of minimally obtrusive technologies but have limitations due to movement artefact, bad sensor coupling, intermittent measurement, and poor-quality recordings compared to gold standard well established methods. Respiratory rate can be derived accurately from pleth recordings in infants. CONCLUSION: Some limitations have been identified in current methods to monitor heart rate and respiratory rate in newborn babies. Novel minimally invasive sensors have advantages that may help clinical practice. Further research studies are needed to assess whether they are sufficiently accurate, practical, and reliable to be suitable for clinical use.

Phenotypic Screening of Histone Deacetylase (HDAC) Inhibitors against Schistosoma mansoni.

Schistosomiasis is a prevalent yet neglected tropical parasitic disease caused by the Schistosoma genus of blood flukes. Praziquantel is the only currently available treatment, hence drug resistance poses a major threat. Recently, histone deacetylase 8 (HDAC8) selective inhibitors have been proposed as a viable treatment for schistosomiasis. Herein, we report the phenotypic screening of a focused library of small molecules of varying HDAC isozyme-inhibition profiles, including eight HDAC8 inhibitors with >10-fold selectivity in comparable functional inhibition assays and IC50 values against HDAC8<100 nM. HDAC8-selective inhibitors showed the lowest potency against Schistosoma mansoni newly transformed schistosomula (NTS). Pan-HDAC inhibitors MMH258, MMH259, and MMH373, as assessed by functional inhibition assays, with minimal or no-observed hHDAC8 and SmHDAC8 activities, were active against both NTS (MMH258, IC50 =1.5 µM; MMH259, IC50 =2.3 µM) and adult S. mansoni (MMH258, IC50 =2.1 µM; MMH373, IC50 =3.4 µM). Our results indicate that neither hHDAC8 nor SmHDAC8 activity were directly correlated to their NTS and adult S. mansoni activities.

Frequency of natural antibodies and concordance analysis for anti-TOXOPLASMA IgM tests in Colombian sera of pregnant women.

Interpretation of IgM anti-Toxoplasma can be problematic given the phenomena of "natural" IgM. We analyzed 1,503 sera obtained during prenatal care program, and we established natural and false-positive results by doing follow-up. In 101 samples the concordance between enzyme linked immunosorbent assay (ELISA) and two semi-automatized systems: electro-chemiluminescence immunoassay (ELECSYS) and vitek immunodiagnostic assay system (VIDAS) was calculated. In 1,503 serum, 71 (4,7%) had ELISA IgG negative and ELISA IgM positive results and in 44 of these had a second sample 4 weeks later. In second samples, 27 (61,3 %) were IgM and IgG negative (false positive result in the first sample) and 13 (29,5%) were ELISA IgM positive and IgG negative (natural IgM). ELISA assay had a poor concordance with enzyme-linked fluorescent immunoassay as well as ELECSYS tests, contrarily, enzyme-linked fluorescent immunoassay and ELECSYS had optimal concordance, with 100 of 101 sera obtaining the same result by both tests. We recommended to use automatized assays to measure IgM anti-Toxoplasma.

Visualization of the Crossroads between a Nascent Infection Thread and the First Cell Division Event in Phaseolus vulgaris Nodulation.

The development of a symbiotic nitrogen-fixing nodule in legumes involves infection and organogenesis. Infection begins when rhizobia enter a root hair through an inward structure, the infection thread (IT), which guides the bacteria towards the cortical tissue. Concurrently, organogenesis takes place by inducing cortical cell division (CCD) at the infection site. Genetic analysis showed that both events are well-coordinated; however, the dynamics connecting them remain to be elucidated. To visualize the crossroads between IT and CCD, we benefited from the fact that, in Phaseolus vulgaris nodulation, where the first division occurs in subepidermal cortical cells located underneath the infection site, we traced a Rhizobium etli strain expressing DsRed, the plant cytokinesis marker YFP-PvKNOLLE, a nuclear stain and cell wall auto-fluorescence. We found that the IT exits the root hair to penetrate an underlying subepidermal cortical (S-E) cell when it is concluding cytokinesis.

Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2.

Writing and erasing of posttranslational modifications are crucial to phenotypic plasticity and antigenic variation of eukaryotic pathogens. Targeting pathogens' modification machineries, thus, represents a valid approach to fighting parasitic diseases. However, identification of parasitic targets and the development of selective anti-parasitic drugs still represent major bottlenecks. Here, we show that the zinc-dependent histone deacetylases (HDACs) of the protozoan parasite Trypanosoma cruzi are key regulators that have significantly diverged from their human counterparts. Depletion of T. cruzi class I HDACs tcDAC1 and tcDAC2 compromises cell-cycle progression and division, leading to cell death. Notably, tcDAC2 displays a deacetylase activity essential to the parasite and shows major structural differences with human HDACs. Specifically, tcDAC2 harbors a modular active site with a unique subpocket targeted by inhibitors showing substantial anti-parasitic effects in cellulo and in vivo. Thus, the targeting of the many atypical HDACs in pathogens can enable anti-parasitic selective chemical impairment.

The structure of the mouse ADAT2/ADAT3 complex reveals the molecular basis for mammalian tRNA wobble adenosine-to-inosine deamination.

Post-transcriptional modification of tRNA wobble adenosine into inosine is crucial for decoding multiple mRNA codons by a single tRNA. The eukaryotic wobble adenosine-to-inosine modification is catalysed by the ADAT (ADAT2/ADAT3) complex that modifies up to eight tRNAs, requiring a full tRNA for activity. Yet, ADAT catalytic mechanism and its implication in neurodevelopmental disorders remain poorly understood. Here, we have characterized mouse ADAT and provide the molecular basis for tRNAs deamination by ADAT2 as well as ADAT3 inactivation by loss of catalytic and tRNA-binding determinants. We show that tRNA binding and deamination can vary depending on the cognate tRNA but absolutely rely on the eukaryote-specific ADAT3 N-terminal domain. This domain can rotate with respect to the ADAT catalytic domain to present and position the tRNA anticodon-stem-loop correctly in ADAT2 active site. A founder mutation in the ADAT3 N-terminal domain, which causes intellectual disability, does not affect tRNA binding despite the structural changes it induces but most likely hinders optimal presentation of the tRNA anticodon-stem-loop to ADAT2.

High frequency of ocular toxoplasmosis in Quindío, Colombia and risk factors related to the infection.

OBJECTIVES: To determine the frequency of retinochoroidal lesions by ocular toxoplasmosis and their relationships with risk factors, in residents of two districts with high exposure to Toxoplasma, in Armenia-Quindío, Colombia. METHODS: Cross-sectional analyses of fundoscopy screening, serological tests, and questionnaires were performed to determine risk factors associated with ocular toxoplasmosis retinochoroidal lesions. Differences in proportions were analyzed using the chi-squared test. RESULTS: Of 161 individuals examined, 17 (10.5%) exhibited retinochoroidal scars suggestive of old inactive Toxoplasma gondii infection. All 17 individuals were seropositive for T. gondii antibodies. Consumption of bottled water was protective against T. gondii infection among individuals in this study. There were no specific epidemiological risk factors associated with ocular toxoplasmosis retinochoroidal lesions. CONCLUSION: Ocular toxoplasmosis is an important cause of visual impairment in Armenia-Quindío, Colombia. The consumption of boiled or bottled water is a major preventive public health measure to reduce infection by T. gondii and the subsequent onset of OT.

Primary Cutaneous Cryptococcosis due to Cryptococcus neoformans in an Immunocompetent Host Treated with Itraconazole and Drainage: Case Report and Review of the Literature.

Cryptococcus neoformans is an opportunistic germ, usually causing infections in immunocompromised patients. The main sources of infection with C. neoformans are excrement from birds, decomposing wood, fruit, and vegetables. Primary cutaneous cryptococcosis (PCC) is a clinical entity, differing from secondary cutaneous cryptococcosis and systematic infection. We report the case of an immunocompetent 60-year-old woman with PCC due to C. neoformans in her right thumb. She reported an accidental injury caused by a rose thorn while she was gardening. Clinical examination showed the presence of an erythematous ulcerated nodule with elevated borders, suppuration, and central necrosis. Skin histology examination showed cutaneous and subcutaneous fibrinoid necrosis with bleeding, abscess, neutrophil-rich cellular infiltration, and the presence of PAS-, Grocott- and mucin-positive spores. The mycological culture showed milky and creamy colonies of C. neoformans after 3 days. As there was no previous history of pulmonary cryptococcosis, we diagnosed PPC. We treated the patient surgically with accurate debridement of nonvital tissues in the right thumb. In addition, we started itraconazole treatment 100 mg twice daily for 6 months, which led to rapid clinical improvement without relapse. PCC is a rare infection that can present with quite unspecific clinical pictures including acneiform lesions, purpura, vesicles, nodules, abscesses, ulcers, granulomas, pustules, draining sinuses, and cellulitis. Prolonged systemic antifungal therapy is necessary in order to get a healing result without relapse. We summarize all the cases of PCC in immunocompetent patients published so far in the literature.

Characterisation of Textile Embedded Electrodes for Use in a Neonatal Smart Mattress Electrocardiography System.

Heart rate monitoring is the predominant quantitative health indicator of a newborn in the delivery room. A rapid and accurate heart rate measurement is vital during the first minutes after birth. Clinical recommendations suggest that electrocardiogram (ECG) monitoring should be widely adopted in the neonatal intensive care unit to reduce infant mortality and improve long term health outcomes in births that require intervention. Novel non-contact electrocardiogram sensors can reduce the time from birth to heart rate reading as well as providing unobtrusive and continuous monitoring during intervention. In this work we report the design and development of a solution to provide high resolution, real time electrocardiogram data to the clinicians within the delivery room using non-contact electric potential sensors embedded in a neonatal intensive care unit mattress. A real-time high-resolution electrocardiogram acquisition solution based on a low power embedded system was developed and textile embedded electrodes were fabricated and characterised. Proof of concept tests were carried out on simulated and human cardiac signals, producing electrocardiograms suitable for the calculation of heart rate having an accuracy within ±1 beat per minute using a test ECG signal, ECG recordings from a human volunteer with a correlation coefficient of ~ 87% proved accurate beat to beat morphology reproduction of the waveform without morphological alterations and a time from application to heart rate display below 6 s. This provides evidence that flexible non-contact textile-based electrodes can be embedded in wearable devices for assisting births through heart rate monitoring and serves as a proof of concept for a complete neonate electrocardiogram monitoring system.

Magnetic Field Triggerable Macroporous PDMS Sponge Loaded with an Anticancer Drug, 5-Fluorouracil.

This study aims to prepare, optimize, and characterize magnetic-field-sensitive sugar-templated polydimethylsiloxane (PDMS) sponges for localized delivery of an anticancer drug, 5-fluorouracil (FLU). For this purpose, different concentrations of carbonyl iron (CI) and magnetite Fe3O4 nanopowders were embedded as magnetosensitive materials in PDMS resins for the fabrication of macroporous sponges via a sugar-template process. The process is environmentally friendly and simple. The fabricated interconnected macroporous magnetic particles loaded PDMS sponges possess flexible skeletons and good recyclability because of their recoverability after compression (deformation) without any breakdown. The prepared magnetic PDMS sponges were evaluated for their morphology (SEM and EDS), porosity (absorbency), elastic modulus, deformation under a magnetic field, thermostability, and in vitro cell studies. All physicochemical and magnetomechanical analysis confirmed that the optimized magnetic-field-sensitive PDMS sponge can provide an efficient method for delivering an on-demand dose of anticancer drug solutions at a specific location and timing with the aid of controlled magnetic fields.

Regioselectively substituted cellulose benzoate propionates for compensation film in optical displays.

Cellulose benzoate propionates (CBzP) were prepared via a staged addition of Pr2O followed by Bz2O to cellulose dissolved in tributylmethylammonium dimethyl phosphate (TBMADMP) providing regioselectively substituted cellulose esters in which the benzoate was preferentially installed at C2 and C3. By systematically varying the DSPr, DSBz, and DSOH (DS = degree of substitution), we synthesized CBzP that could potentially be utilized as a unique compensation film in optical displays.

A component analysis of awareness training for reducing speech disfluencies.

Recent literature supports using an awareness training treatment package to decrease speech disfluencies for college students delivering short speeches. This package includes identifying speech disfluencies first via a video recording (video training), then during in vivo speech practice (in vivo training). However, the literature lacks an evaluation of these subcomponents, which poses a barrier to better understanding the efficiency, social validity, and potential underlying behavioral principles of awareness training. We conducted an add-in component analysis with 8 college students by implementing either video or in vivo training first, evaluating treatment effects via a posttest, then implementing the remaining subcomponent, if warranted. We found that in vivo speech practice may be sufficient for reducing disfluencies for some participants, but a treatment package including the sequential application of both video and in vivo training is more likely to result in marked behavior change.

Rhizobium etli CE3-DsRed pMP604: a useful biological tool to study initial infection steps in Phaseolus vulgaris nodulation.

MAIN CONCLUSION: Rhizobium etli CE3-DsRed pMP604 drives infection 12-24 h earlier than R. etli CE3-DsRed and it is an excellent tool in live-cell imaging studies of IT developement in P. vulgaris roots. The study of the cellular dynamics of nodulation has frequently been limited by the difficulty of performing live-cell imaging in nodule primordia and legume roots, which are constituted by multiple cell layers, such is the case of Phaseolus vulgaris. Seeking conditions to reduce the time it takes for rhizobia to infect P. vulgaris root, we decided to explore the nodulation properties of Rhizobium etli CE3 pMP604, a strain that constitutively produces Nod factors through a flavonoids-independent transcriptional activation which is often used to purify Nod factors. Even though the strain infects 12-24 h earlier than the parental R. etli CE3 strain, infection thread (IT) formation, nodule organogenesis processes and N2-fixation activity are similar for both strains. Additionally, we have confirmed that R. etli CE3-DsRed pMP604 is an excellent tool to trace IT development in P. vulgaris roots.

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1.

Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines.