Selective Inhibition of mTORC1 Signaling Supports the Development and Maintenance of Pluripotency.

Insight into the molecular mechanisms governing the development and maintenance of pluripotency is important for understanding early development and the use of stem cells in regenerative medicine. We demonstrate the selective inhibition of mTORC1 signaling is important for developing the inner cell mass (ICM) and the self-renewal of human embryonic stem cells. S6K suppressed the expression and function of pluripotency-related transcription factors (PTFs) OCT4, SOX2, and KLF4 through phosphorylation and ubiquitin proteasome-mediated protein degradation, indicating that S6K inhibition is required for pluripotency. PTFs inhibited mTOR signaling. The phosphorylation of S6 was decreased in PTF-positive cells of the ICM in embryos. Activation of mTORC1 signaling blocked ICM formation and the selective inhibition of S6K by rapamycin increased the ICM size in mouse blastocysts. Thus, selective inhibition of mTORC1 signaling supports the development and maintenance of pluripotency.

Electroencephalography microstates highlight specific mindfulness traits.

The present study aimed to investigate the spontaneous dynamics of large-scale brain networks underlying mindfulness as a dispositional trait, through resting-state electroencephalography (EEG) microstates analysis. Eighteen participants had attended a standardized mindfulness-based stress reduction training (MBSR), and 18 matched waitlist individuals (CTRL) were recorded at rest while they were passively exposed to auditory stimuli. Participants' mindfulness traits were assessed with the Five Facet Mindfulness Questionnaire (FFMQ). To further explore the relationship between microstate dynamics at rest and mindfulness traits, participants were also asked to rate their experience according to five phenomenal dimensions. After training, MBSR participants showed a highly significant increase in FFMQ score, as well as higher observing and non-reactivity FFMQ sub-scores than CTRL participants. Microstate analysis revealed four classes of microstates (A-D) in global clustering across all subjects. The MBSR group showed lower duration, occurrence and coverage of microstate C than the control group. Moreover, these microstate C parameters were negatively correlated to non-reactivity sub-scores of FFMQ across participants, whereas the microstate A occurrence was negatively correlated to FFMQ total score. Further analysis of participants' self-reports suggested that MBSR participants showed a better sensory-affective integration of auditory interferences. In line with previous studies, our results suggest that temporal dynamics of microstate C underlie specifically the non-reactivity trait of mindfulness. These findings encourage further research into microstates in the evaluation and monitoring of the impact of mindfulness-based interventions on the mental health and well-being of individuals.

Systematics and life cycles of four avian schistosomatids from Southern Cone of South America.

Relative to the numerous studies focused on mammalian schistosomes, fewer include avian schistosomatids particularly in the southern hemisphere. This is changing and current research emerging from the Neotropics shows a remarkable diversity of endemic taxa. To contribute to this effort, nine ducks (Spatula cyanoptera, S.versicolor, Netta peposaca), 12 swans (Cygnus melancoryphus) and 1,400 Physa spp. snails from Chile and Argentina were collected for adults and larval schistosomatids, respectively. Isolated schistosomatids were preserved for morphological and molecular analyses (28S and COI genes). Four different schistosomatid taxa were retrieved from birds: Trichobilharzia sp. in N. peposaca and S. cyanoptera that formed a clade; S.cyanoptera and S. versicolor hosted Trichobilharzia querquedulae; Cygnus melancoryphus hosted the nasal schistosomatid, Nasusbilharzia melancorhypha; and one visceral, Schistosomatidae gen. sp., which formed a clade with furcocercariae from Argentina and Chile from previous work. Of the physid snails, only one from Argentina had schistosomatid furcocercariae that based on molecular analyses grouped with T. querquedulae. This study represents the first description of adult schistosomatids from Chile as well as the elucidation of the life cycles of N.melancorhypha and T. querquedulae in Chile and Neotropics, respectively. Without well-preserved adults, the putative new genus Schistosomatidae gen. sp. could not be described, but its life cycle involves Chilina spp. and C. melancoryphus. Scanning electron microscopy of T. querquedulae revealed additional, undescribed morphological traits, highlighting its diagnostic importance. Authors stress the need for additional surveys of avian schistosomatids from the Neotropics to better understand their evolutionary history.

Relationship between cognition and age at onset of first-episode psychosis: comparative study between adolescents, young adults, and adults.

Psychotic disorders typically manifest from late adolescence to early adulthood, and an earlier onset might be associated with greater symptom severity and a worse long-term prognosis. This study aimed to compare the cognitive characteristics of patients with first-episode psychosis (FEP) by their age at onset. We included 298 patients diagnosed with FEP and classified them as having an early onset (EOS), youth onset (YOS), or adult onset (AOS) based on age limits of ≤ 18 years (N = 61), 19-24 years (N = 121), and ≥ 25 years (N = 116), respectively. Socio-demographic and clinical variables included age at baseline, gender, socio-economic status, antipsychotic medication, DSM-IV diagnoses assessed by clinical semi-structured interview, psychotic symptom severity, and age at onset. Neuropsychological assessment included six cognitive domains: premorbid intelligence, working memory, processing speed, verbal memory, sustained attention, and executive functioning. The EOS group had lower scores than the YOS or AOS groups in global cognition, executive functioning, and sustained attention. Although the scores in the YOS group were intermediate to those in the EOS and AOS groups for most cognitive factors, no statistically significant differences were detected between the YOS and AOS groups. Age at onset results in specific patterns of cognitive interference. Of note, impairment appears to be greater with EOS samples than with either YOS or AOS samples. A longitudinal study with a larger sample size is needed to confirm our findings.

Tetrathyridia in an endemic lizard from Chile: molecular evidence for South America.

Mesocestoides is a controversial tapeworm with significant lack of data related to systematics and life cycles. This helminth has an indirect life cycle with vertebrates, mostly carnivorous mammals, as definitive hosts. Theoretically, a coprophagous arthropod would be the first intermediate host, and herptiles, mammals, and birds, which prey on these insects, would represent the second intermediate hosts. However, recent evidence suggests that this life cycle would require only two hosts, with no arthropods involved. In the Neotropics, although there are records of mammals and reptiles as hosts for Mescocestoides, no molecular analyses have been performed. This work aimed to record an additional intermediate host and molecularly characterize the isolated larvae. Thus, 18 braided tree iguanas (Liolaemus platei) from Northern Chile were collected and dissected during 2019. One lizard was parasitized by three morphotypes of larvae compatible with tetrathyridia of Mescocestoides. To achieve its specific identity, a molecular approach was performed: 18S rRNA and 12S rRNA loci were amplified through cPCR. The inferred phylogenies confirmed the morphological diagnosis and stated that all morphotypes were conspecifics. The sequences for both loci formed a monophyletic clade with high nodal support, representing a sister taxon to Mescocestoides clade C. This study represents the first molecular characterization of any taxon of Mescocestoides from the Neotropics. Future surveys from potential definitive hosts would help to elucidate its life cycle. Furthermore, an integrative taxonomic approach is required in additional studies from the Neotropical region, which would contribute to a better understanding of the evolutionary relationships of this genus.

A framework for mapping and monitoring human-ocean interactions in near real-time during COVID-19 and beyond.

The human response to the COVID-19 pandemic set in motion an unprecedented shift in human activity with unknown long-term effects. The impacts in marine systems are expected to be highly dynamic at local and global scales. However, in comparison to terrestrial ecosystems, we are not well-prepared to document these changes in marine and coastal environments. The problems are two-fold: 1) manual and siloed data collection and processing, and 2) reliance on marine professionals for observation and analysis. These problems are relevant beyond the pandemic and are a barrier to understanding rapidly evolving blue economies, the impacts of climate change, and the many other changes our modern-day oceans are undergoing. The "Our Ocean in COVID-19″ project, which aims to track human-ocean interactions throughout the pandemic, uses the new eOceans platform (eOceans.app) to overcome these barriers. Working at local scales, a global network of ocean scientists and citizen scientists are collaborating to monitor the ocean in near real-time. The purpose of this paper is to bring this project to the attention of the marine conservation community, researchers, and the public wanting to track changes in their area. As our team continues to grow, this project will provide important baselines and temporal patterns for ocean conservation, policy, and innovation as society transitions towards a new normal. It may also provide a proof-of-concept for real-time, collaborative ocean monitoring that breaks down silos between academia, government, and at-sea stakeholders to create a stronger and more democratic blue economy with communities more resilient to ocean and global change.

Higher frequency of hospitalization but lower relative mortality for pandemic influenza in people with type 2 diabetes.

BACKGROUND: There is limited evidence linking type 2 diabetes (T2D) to influenza-related complications. OBJECTIVES: To test a set of research questions relating to pandemic influenza vaccination, hospitalization and mortality in people with and without T2D. METHODS: In this population-based cohort study, we linked individual-level data from several national registers for all Norwegian residents aged 30 years or more as of January 2009. People with or without T2D at baseline (n = 2 992 228) were followed until December 2013. We used Cox regression to estimate adjusted hazard ratios (aHRs). RESULTS: Pandemic influenza hospitalization was more common in individuals with T2D (aHR = 2.46, 95% CI 2.04-2.98). The mortality hazard ratio associated with hospitalization for pandemic influenza was lower in people with T2D (aHR = 1.82, 95% CI 1.21-2.74) than in those without T2D (aHR = 3.89, 95% CI 3.27-4.62). The same pattern was observed when restricting to 90-day mortality (aHR = 3.89, 95% CI 1.25-12.06 amongst those with T2D and aHR = 10.79, 95% CI 7.23-16.10 amongst those without T2D). The rate of hospitalization for pandemic influenza was 78% lower in those vaccinated compared to nonvaccinated amongst people with T2D (aHR = 0.22, 95% CI 0.11-0.39), whilst the corresponding estimate for those without T2D was 59% lower (aHR = 0.41, 95% CI 0.33-0.52). Mortality was 25% lower in those vaccinated compared to nonvaccinated amongst people with T2D (aHR = 0.75, 95% CI 0.73-0.77), whilst the corresponding estimate for those without T2D was 9% (aHR = 0.91, 95% CI 0.90-0.92). CONCLUSIONS: There may have been a lower threshold for pandemic influenza hospitalization for people with T2D, rather than more severe influenza infection. Our combined results support the importance of influenza vaccination amongst people with T2D, especially during pandemics.

Coherent imager module with a large field of view for synthetic aperture interferometry applications.

Optical areal profilometry of large precision-engineered surfaces require high-resolution measurements over large fields of view. Synthetic Aperture Interferometry (SAI) offers an alternative to the conventional approach of stitching small fields of view (FOV) obtained with Coherent Scanning Interferometry (CSI) using high-NA objectives. In SAI, low-resolution digital holograms are recorded for different illumination and observation directions and they are added coherently to produce a high-resolution reconstruction over a large FOV. This paper describes the design, fabrication and characterization of a large FOV, compact and low-cost coherent imager (CI) as a building block of a coherent sensor array for a SAI system. The CI consists of a CMOS photodetector array with 1.12 µm pixel pitch, a square entrance pupil and a highly divergent reference beam that emerges from a pinhole milled with a focused ion beam on the cylindrical cladding at the tip of an optical fibre. In order to accurately reconstruct the digital holograms, the wavefront of the reference beam is estimated by localizing the reference source relative to the photodetector array. This is done using an optimization approach that simultaneously reconstructs plane waves that reach the aperture from 121 different illumination directions and guarantees a phase root-mean-squared (RMS) error of less than a fifth of the wavelength across the CI entrance pupil at a boundary of the FOV. The CI performance is demonstrated with a holographic reconstruction of a 0.110 m wide object placed at a distance of 0.085 m, i.e. a FOV = ±0.57 rad, the highest reported to date with a holographic camera.

On the Discoloration of Methylene Blue by Visible Light.

The discoloration of methylene blue in aqueous solution was studied under illumination by a fluorescent lamp, LEDs of red, green, and blue light, and a UV-A black light bulb. Overall results showed that methylene blue was discolored with and without the presence of any photoactive semiconductor. Outcomes depended on the combination substrate-light source employed. Photosensitization was assumed as the discoloration mechanism followed upon visible light irradiation. Fluorescence spectroscopy and high-performance liquid chromatography were used to investigate the possible intermediates formed in the irradiated solutions. The detailed nature of formed species was not stablished, but it was proved that the dye molecule photo-bleached and partially defragmented in several intermediates including leuco dyes, demethylated phenothiazine dyes, and probably humic substances. Since the fluorescence intermediates found were similar for most of the irradiated solutions, it was assumed that comparable reactive species were responsible for the discoloration of the molecule in solution. Results proved the misconception of discoloration experiments found in the literature when employing visible light near the absorption region of the dye.

Screening for Zika virus in deceased organ donors in Florida.

Zika virus (ZIKV) cases have been detected across the United States (US) and locally acquired cases have been reported in Florida. Currently, there are no ZIKV screening guidelines and no data on the incidence among organ donors in the US. This retrospective study was conducted at Jackson Memorial-Miami Transplant Institute. Positive ZIKV tests in local deceased organ donors were investigated from 6/2016 to 1/2017. We evaluated demographics and risk factors for ZIKV infection among organ donors and transplant outcomes among recipients of donors with positive ZIKV testing. One hundred forty-two donors were analyzed. Ten percent had traveled to ZIKV-endemic countries and 19% had outdoor occupations. Only 3% had positive ZIKV IGG. None had a positive ZIKV IGM or PCR. ZIKV-positive donors were more likely to have traveled to ZIKV-endemic countries (50% vs. 9%, P = .05). The kidneys from a ZIKV-positive donor were transplanted in our hospital with no 6-month rejection, graft failure, or death in the recipients. Our study demonstrated a low prevalence of ZIKV among deceased donors in our community. Despite local ZIKV transmission, ZIKV was more common in donors who traveled to ZIKV-endemic countries. This cohort demonstrated excellent outcomes in recipients of ZIKV IGG-positive donors. However, larger studies are needed.

Mannose-Binding Lectin-Deficient Donors Increase the Risk of Bacterial Infection and Bacterial Infection-Related Mortality After Liver Transplantation.

Mannose-binding lectin (MBL) is synthesized by the liver and binds to microbes. MBL2 gene polymorphisms produce intermediate/low/null or normal MBL serum levels (MBL-deficient or MBL-sufficient phenotypes, respectively). We aimed to evaluate the incidence and severity of infection, rejection, and survival within 1 year after liver transplantation (LT) according to donor and recipient MBL2 gene polymorphisms. A repeated-event analysis for infection episodes (negative binomial regression, Andersen-Gill model) was performed in 240 LTs. Four hundred twenty-eight infectious episodes (310 bacterial, 15 fungal, 65 cytomegalovirus [CMV]-related, and 38 viral non-CMV-related episodes) and 48 rejection episodes were recorded. The main bacterial infections were urinary (n = 82, 26%) and pneumonia (n = 69, 22%). LT recipients of MBL-deficient livers had a higher risk of bacterial infection (incidence rate ratio [IRR] 1.48 [95% confidence interval 1.04-2.09], p = 0.028), pneumonia (IRR 2.4 [95% confidence interval 1.33-4.33], p = 0.013), and septic shock (IRR 5.62 [95% confidence interval 1.92-16.4], p = 0.002) compared with recipients of MBL-deficient livers. The 1-year bacterial infection-related mortality was higher in recipients of MBL-deficient versus MBL-sufficient livers (65.8% vs. 56.1%, respectively; p = 0.0097). The incidence of rejection, viral, or fungal infection was similar in both groups. Recipient MBL2 genotype did not significantly increase the risk of bacterial infection. LT recipients of MBL-deficient livers have a higher risk of bacterial infection, pneumonia, septic shock, and 1-year bacterial infection-related mortality after LT.

BCL-2 levels do not predict azathioprine treatment response in inflammatory bowel disease, but inhibition induces lymphocyte apoptosis and ameliorates colitis in mice.

In inflammatory bowel disease (IBD), inflammation is sustained by an exaggerated response of lymphocytes. This results from enhanced expression of anti-apoptotic B cell lymphoma (BCL-2) and BCL-XL associated with a diminished turnover. Azathioprine (AZA) directly targets BCL-2 family-mediated apoptosis. We investigated whether the BCL-2 family expression pattern could be used to predict treatment response to AZA and determined whether BCL-2 inhibitor A-1211212 effectively diminishes lymphocytes and ameliorates inflammation in a model of colitis. BCL-2 family expression pattern was determined by next-generation sequencing (NGS). BCL-2 inhibitor was administered orally to Il10-/- mice. Haematological analyses were performed with an ADVIA 2120 and changes in immune cells were investigated using quantitative polymerase chain reaction (qPCR) and fluorescence activated cell sorter (FACS). We determined similar expression levels of BCL-2 family members in patients with remission and patients refractory to treatment, showing that BCL-2 family expression can not predict AZA treatment response. Expression was not correlated with the modified Truelove and Witts activity index (MTWAI). BCL-2 inhibitor initiated cell death in T cells from patients refractory to AZA and reduced lymphocyte count in Il10-/- mice. FACS revealed diminished CD8+ T cells upon BCL-2 inhibitor in Il10-/- mice without influencing platelets. Tnf, Il1ß, IfnƔ and Mcp-1 were decreased upon BCL-2 inhibitor. A-1211212 positively altered the colonic mucosa and ameliorated inflammation in mice. Pro-apoptotic BCL-2 inhibitor A-1211212 diminishes lymphocytes and ameliorates colitis in Il10-/- mice without inducing thrombocytopenia. BCL-2 inhibition could be a new therapy option for patients refractory to AZA.

Assessment of chemical and microbiological parameters of indoor swimming pool atmosphere using multiple comparisons.

The aim of this study was to evaluate the air quality of an indoor swimming pool, analyzing diurnal and seasonal variations in microbiological counts and chemical parameters. The results indicated that yeast and bacteria counts, as well as carbon dioxide (CO2 ), nitrogen oxides (NOx ) and O3 concentrations, showed significant diurnal difference. On the other hand, temperature, relative humidity (R.H.), yeast counts and concentrations of CO2 , particles, O3 , toluene, and benzene showed seasonal differences. In addition, the relationship between indoor and outdoor air and the degree of correlation between the different parameters have been calculated, suggesting that CO2 , fine particles and NOx would have indoor origin due to the human activity and secondary reactions favored by the chemical and environmental conditions of the swimming pool; while O3 , benzene and toluene, would come from outside, mainly. The overall results indicated that indoor air quality (IAQ) in the swimming pool building was deficient by the high levels of CO2 and microorganisms, low temperatures, and high R.H., because frequently the limits established by the legislation were exceeded. This fact could be due to the poor ventilation and the inadequate operation of heating, ventilation, and air-conditioning systems.

Characterization of the reference wave in a compact digital holographic camera.

A hologram is a recording of the interference between an unknown object wave and a coherent reference wave. Providing the object and reference waves are sufficiently separated in some region of space and the reference beam is known, a high-fidelity reconstruction of the object wave is possible. In traditional optical holography, high-quality reconstruction is achieved by careful reillumination of the holographic plate with the exact same reference wave that was used at the recording stage. To reconstruct high-quality digital holograms the exact parameters of the reference wave must be known mathematically. This paper discusses a technique that obtains the mathematical parameters that characterize a strongly divergent reference wave that originates from a fiber source in a new compact digital holographic camera. This is a lensless design that is similar in principle to a Fourier hologram, but because of the large numerical aperture, the usual paraxial approximations cannot be applied and the Fourier relationship is inexact. To characterize the reference wave, recordings of quasi-planar object waves are made at various angles of incidence using a Dammann grating. An optimization process is then used to find the reference wave that reconstructs a stigmatic image of the object wave regardless of the angle of incidence.

Effectiveness and safety of ombitasvir, paritaprevir, ritonavir ± dasabuvir ± ribavirin: An early access programme for Spanish patients with genotype 1/4 chronic hepatitis C virus infection.

Over the last 5 years, therapies for hepatitis C virus (HCV) infection have improved significantly, achieving sustained virologic response (SVR) rates of up to 100% in clinical trials in patients with HCV genotype 1. We investigated the effectiveness and safety of ombitasvir/paritaprevir/ritonavir±dasabuvir in an early access programme. This was a retrospective, multicentre, national study that included 291 treatment-naïve and treatment-experienced patients with genotype 1 or 4 HCV infection. Most patients (65.3%) were male, and the mean age was 57.5 years. The mean baseline viral load was 6.1 log, 69.8% had HCV 1b genotype, 72.9% had cirrhosis and 34.7% were treatment-naïve. SVR at 12 weeks posttreatment was 96.2%. Four patients had virological failure (1.4%), one leading to discontinuation. There were no statistical differences in virological response according to genotype or liver fibrosis. Thirty patients experienced serious adverse events (SAEs) (10.3%), leading to discontinuation in six cases. Hepatic decompensation was observed in five patients. Four patients died during treatment or follow-up, three of them directly related to liver failure. Multivariate analyses showed a decreased probability of achieving SVR associated with baseline albumin, bilirubin and Child-Pugh score B, and a greater probability of developing SAEs related to age and albumin. This combined therapy was highly effective in clinical practice with an acceptable safety profile and low rates of treatment discontinuation.

Impact of Chiropractic Manipulation on Bone and Skeletal Muscle of Ovariectomized Rats.

Evidence suggests that chiropractic manipulation might exert positive effects in osteoporotic patients. The aim of this study was to evaluate the effects of chiropractic manipulation on bone structure and skeletal muscle in rats with bone loss caused by ovariectomy (OVX). The 6-month old Sprague-Dawley rats at 10 weeks following OVX or sham operation (Sh) did not suffer chiropractic manipulation (NM group) or were submitted to true chiropractic manipulation using the chiropractic adjusting instrument Activator V® three times/week for 6 weeks as follows: Force 1 setting was applied onto the tibial tubercle of the rat right hind limb (TM group), whereas the corresponding left hind limb received a false manipulation (FM group) consisting of ActivatorV® firing in the air and slightly touching the tibial tubercle. Bone mineral density (BMD) and bone mineral content (BMC) were determined in long bones and L3-L4 vertebrae in all rats. Femora and tibia were analyzed by µCT. Mechano growth factor (MGF) was detected in long bones and soleus, quadriceps and tibial muscles by immunohistochemistry and Western blot. The decrease of BMD and BMC as well as trabecular bone impairment in the long bones of OVX rats vs Sh controls was partially reversed in the TM group versus FM or NM rats. This bone improvement by chiropractic manipulation was associated with an increased MGF expression in the quadriceps and the anterior tibial muscle in OVX rats. These findings support the notion that chiropractic manipulation can ameliorate osteoporotic bone at least partly by targeting skeletal muscle.

Neurologic emergencies in HIV-negative immunosuppressed patients. / Urgencias neurológicas en el paciente inmunosuprimido no VIH.

HIV-negative immunosuppressed patients comprise a heterogeneous group including transplant patients, patients undergoing treatment with immunosuppressors, uremic patients, alcoholics, undernourished patients, diabetics, patients on dialysis, elderly patients, and those diagnosed with severe or neoplastic processes. Epileptic seizures, focal neurologic signs, and meningoencephalitis are neurologic syndromes that require urgent action. In most of these situations, neuroimaging tests are necessary, but the findings can be different from those observed in immunocompetent patients in function of the inflammatory response. Infectious disease is the first diagnostic suspicion, and the identification of an opportunistic pathogen should be oriented in function of the type and degree of immunosuppression. Other neurologic emergencies include ischemic stroke, cerebral hemorrhage, neoplastic processes, and pharmacological neurotoxicity. This article reviews the role of neuroimaging in HIV-negative immunodepressed patients with a neurologic complication that requires urgent management.

Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas-Kidney Transplants.

Patients with type 1 diabetes (T1D) who are recipients of pancreas transplants are believed to rarely develop T1D recurrence in the allograft if effectively immunosuppressed. We evaluated a cohort of 223 recipients of simultaneous pancreas-kidney allografts for T1D recurrence and its risk factors. With long-term follow-up, recurrence was observed in approximately 7% of patients. Comparing the therapeutic regimens employed in this cohort over time, lack of induction therapy was associated with recurrence, but this occurs even with the current regimen, which includes induction; there was no influence of maintenance regimens. Longitudinal testing for T1D-associated autoantibodies identified autoantibody positivity, number of autoantibodies, and autoantibody conversion after transplantation as critical risk factors. Autoantibodies to the zinc transporter 8 had the strongest and closest temporal association with recurrence, which was not explained by genetically encoded amino acid sequence donor-recipient mismatches for this autoantigen. Genetic risk factors included the presence of the T1D-predisposing HLA-DR3/DR4 genotype in the recipient and donor-recipient sharing of HLA-DR alleles, especially HLA-DR3. Thus, T1D recurrence is not uncommon and is developing in patients treated with current immunosuppression. The risk factors identified in this study can be assessed in the transplant clinic to identify recurrent T1D and may lead to therapeutic advances.