Disposition of Federally Owned Surpluses

PDZ domains are scaffolding modules in protein-protein interactions that mediate numerous physiological functions by interacting canonically with the C-terminus or non-canonically with an internal motif of protein ligands. A conserved carboxylate-binding site in the PDZ domain facilitates binding via backbone hydrogen bonds; however, little is known about the role of these hydrogen bonds due to experimental challenges with backbone mutations. Here we address this interaction by generating semisynthetic PDZ domains containing backbone amide-to-ester mutations and evaluating the importance of individual hydrogen bonds for ligand binding. We observe substantial and differential effects upon amide-to-ester mutation in PDZ2 of postsynaptic density protein 95 and other PDZ domains, suggesting that hydrogen bonding at the carboxylate-binding site contributes to both affinity and selectivity. In particular, the hydrogen-bonding pattern is surprisingly different between the non-canonical and canonical interaction. Our data provide a detailed understanding of the role of hydrogen bonds in protein-protein interactions

Influence of health literacy on maintenance of exclusive breastfeeding at 6 months postpartum: a multicentre study

Background: International organizations recommend initiating breastfeeding within the first hour of life and maintaining exclusive breastfeeding for the first 6 months. However, worldwide rates of exclusive breastfeeding for 6-month-old infants is far from meeting the goal proposed by the World Health Organization, which is to reach a minimum of 50% of infants. Education is one of the factors affecting the initiation and continuation of breastfeeding, and incidentally, it is also related to lower health literacy. This study explored the influence of health literacy on maintenance of exclusive breastfeeding at 6 months postpartum. Methods: A longitudinal multicenter study with 343 women were recruited between January 2019 and January 2020. The first questionnaire was held during the puerperium (24–48 h) with mothers practicing exclusive breastfeeding, with whom 6-month postpartum breastfeeding follow-up was performed. Socio-demographic, clinical and obstetric variables were collected. Breastfeeding efficiency was assessed using the LATCH breastfeeding assessment tool. The health literacy level was evaluated by the Newest Vital Sign screening tool. A multivariate logistic regression model was used to detect protective factors for early exclusive breastfeeding cessation. Results: One third of the women continued exclusive breastfeeding at 6 months postpartum. Approximately half the participants had a low or inadequate health literacy level. An adequate health literacy level, a high LATCH breastfeeding assessment tool score (>9 points) and being married were the protective factors against exclusive breastfeeding cessation at 6 months postpartum. Conclusion: Health literacy levels are closely related to maintaining exclusive breastfeeding and act as a protective factor against early cessation. A specific instrument is needed to measure the lack of “literacy in breastfeeding”, in order to verify the relationship between health literacy and maintenance of exclusive breastfeedin

The Interaction between the First Transmembrane Domain and the Thumb of ASIC1a Is Critical for Its N-Glycosylation and Trafficking

Acid-sensing ion channel-1a (ASIC1a), the primary proton receptor in the brain, contributes to multiple diseases including stroke, epilepsy and multiple sclerosis. Thus, a better understanding of its biogenesis will provide important insights into the regulation of ASIC1a in diseases. Interestingly, ASIC1a contains a large, yet well organized ectodomain, which suggests the hypothesis that correct formation of domain-domain interactions at the extracellular side is a key regulatory step for ASIC1a maturation and trafficking. We tested this hypothesis here by focusing on the interaction between the first transmembrane domain (TM1) and the thumb of ASIC1a, an interaction known to be critical in channel gating. We mutated Tyr71 and Trp287, two key residues involved in the TM1-thumb interaction in mouse ASIC1a, and found that both Y71G and W287G decreased synaptic targeting and surface expression of ASIC1a. These defects were likely due to altered folding; both mutants showed increased resistance to tryptic cleavage, suggesting a change in conformation. Moreover, both mutants lacked the maturation of N-linked glycans through mid to late Golgi. These data suggest that disrupting the interaction between TM1 and thumb alters ASIC1a folding, impedes its glycosylation and reduces its trafficking. Moreover, reducing the culture temperature, an approach commonly used to facilitate protein folding, increased ASIC1a glycosylation, surface expression, current density and slowed the rate of desensitization. These results suggest that correct folding of extracellular ectodomain plays a critical role in ASIC1a biogenesis and function

Influence of Health Literacy on Maintenance of Exclusive Breastfeeding at 6 Months Postpartum: A Multicentre Study

Data Availability Statement: Please note that the database is in an open repository. You can access the data through this link: http://hdl.handle.net/10234/196606 (accessed on 20 February 2022).Copyright © 2022 by the authors. Background: International organizations recommend initiating breastfeeding within the first hour of life and maintaining exclusive breastfeeding for the first 6 months. However, worldwide rates of exclusive breastfeeding for 6-month-old infants is far from meeting the goal proposed by the World Health Organization, which is to reach a minimum of 50% of infants. Education is one of the factors affecting the initiation and continuation of breastfeeding, and incidentally, it is also related to lower health literacy. This study explored the influence of health literacy on maintenance of exclusive breastfeeding at 6 months postpartum. Methods: A longitudinal multicenter study with 343 women were recruited between January 2019 and January 2020. The first questionnaire was held during the puerperium (24–48 h) with mothers practicing exclusive breastfeeding, with whom 6-month postpartum breastfeeding follow-up was performed. Socio-demographic, clinical and obstetric variables were collected. Breastfeeding efficiency was assessed using the LATCH breastfeeding assessment tool. The health literacy level was evaluated by the Newest Vital Sign screening tool. A multivariate logistic regression model was used to detect protective factors for early exclusive breastfeeding cessation. Results: One third of the women continued exclusive breastfeeding at 6 months postpartum. Approximately half the participants had a low or inadequate health literacy level. An adequate health literacy level, a high LATCH breastfeeding assessment tool score (>9 points) and being married were the protective factors against exclusive breastfeeding cessation at 6 months postpartum. Conclusion: Health literacy levels are closely related to maintaining exclusive breastfeeding and act as a protective factor against early cessation. A specific instrument is needed to measure the lack of “literacy in breastfeeding”, in order to verify the relationship between health literacy and maintenance of exclusive breastfeeding.Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) for the conduction of II Grant on Nursing I&D&I 2020 (UGP-20-250)

Using a Non-Image-Based Medium-Throughput Assay for Screening Compounds Targeting N-myristoylation in Intracellular Leishmania Amastigotes

We have refined a medium-throughput assay to screen hit compounds for activity against N-myristoylation in intracellular amastigotes of Leishmania donovani. Using clinically-relevant stages of wild type parasites and an Alamar blue-based detection method, parasite survival following drug treatment of infected macrophages is monitored after macrophage lysis and transformation of freed amastigotes into replicative extracellular promastigotes. The latter transformation step is essential to amplify the signal for determination of parasite burden, a factor dependent on equivalent proliferation rate between samples. Validation of the assay has been achieved using the anti-leishmanial gold standard drugs, amphotericin B and miltefosine, with EC50 values correlating well with published values. This assay has been used, in parallel with enzyme activity data and direct assay on isolated extracellular amastigotes, to test lead-like and hit-like inhibitors of Leishmania Nmyristoyl transferase (NMT). These were derived both from validated in vivo inhibitors of Trypanosoma brucei NMT and a recent high-throughput screen against L. donovani NMT. Despite being a potent inhibitor of L. donovani NMT, the activity of the lead T. brucei NMT inhibitor (DDD85646) against L. donovani amastigotes is relatively poor. Encouragingly, analogues of DDD85646 show improved translation of enzyme to cellular activity. In testing the high-throughput L. donovani hits, we observed macrophage cytotoxicity with compounds from two of the four NMT-selective series identified, while all four series displayed low enzyme to cellular translation, also seen here with the T. brucei NMT inhibitors. Improvements in potency and physicochemical properties will be required to deliver attractive lead-like Leishmania NMT inhibitors

The Evolution of a Female Genital Trait Widely Distributed in the Lepidoptera: Comparative Evidence for an Effect of Sexual Coevolution

Sexual coevolution is considered responsible for the evolution of many male genital traits, but its effect on female genital morphology is poorly understood. In many lepidopterans, females become temporarily unreceptive after mating and the length of this refractory period is inversely related to the amount of spermatophore remaining in their genital tracts. Sperm competition can select for males that delay female remating by transferring spermatophores with thick spermatophore envelopes that take more time to be broken. These envelopes could select for signa, sclerotized sharp structures located within the female genital tract, that are used for breaking spermatophores. Thus, this hypothesis predicts that thick spermatophore envelopes and signa evolve in polyandrous species, and that these adaptations are lost when monandry evolves subsequently. Here we test the expected associations between female mating pattern and presence/absence of signa, and review the scant information available on the thickness of spermatophore envelopes.We made a literature review and found information on female mating pattern (monandry/polyandry), presence/absence of signa and phylogenetic position for 37 taxa. We built a phylogenetic supertree for these taxa, mapped both traits on it, and tested for the predicted association by using Pagel's test for correlated evolution. We found that, as predicted by our hypothesis, monandry evolved eight times and in five of them signa were lost; preliminary evidence suggests that at least in two of the three exceptions males imposed monandry on females by means of specially thick spermatophore envelopes. Previously published data on six genera of Papilionidae is in agreement with the predicted associations between mating pattern and the characteristics of spermatophore envelopes and signa.Our results support the hypothesis that signa are a product of sexually antagonistic coevolution with spermatophore envelopes

Comparison of two independent systematic reviews of trials of recombinant human bone morphogenetic protein-2 (rhBMP-2) : The Yale Open Data Access Medtronic Project

Background: It is uncertain whether the replication of systematic reviews, particularly those with the same objectives and resources, would employ similar methods and/or arrive at identical findings. We compared the results and conclusions of two concurrent systematic reviews undertaken by two independent research teams provided with the same objectives, resources, and individual participant-level data. Methods: Two centers in the USA and UK were each provided with participant-level data on 17 multi-site clinical trials of recombinant human bone morphogenetic protein-2 (rhBMP-2). The teams were blinded to each other's methods and findings until after publication. We conducted a retrospective structured comparison of the results of the two systematic reviews. The main outcome measures included (1) trial inclusion criteria; (2) statistical methods; (3) summary efficacy and risk estimates; and (4) conclusions. Results: The two research teams' meta-analyses inclusion criteria were broadly similar but differed slightly in trial inclusion and research methodology. They obtained similar results in summary estimates of most clinical outcomes and adverse events. Center A incorporated all trials into summary estimates of efficacy and harms, while Center B concentrated on analyses stratified by surgical approach. Center A found a statistically significant, but small, benefit whereas Center B reported no advantage. In the analysis of harms, neither showed an increased cancer risk at 48 months, although Center B reported a significant increase at 24 months. Conclusions reflected these differences in summary estimates of benefit balanced with small but potentially important risk of harm. Conclusions: Two independent groups given the same research objectives, data, resources, funding, and time produced broad general agreement but differed in several areas. These differences, the importance of which is debatable, indicate the value of the availability of data to allow for more than a single approach and a single interpretation of the data. Systematic review registration: PROSPERO CRD42012002040and CRD42012001907

Evolución de los niveles de condición física en población octogenaria y su relación con un estilo de vida sedentario

Objetivos: Determinar los cambios que se producen enla condición física a lo largo de dos años de seguimiento enoctogenarios y comprobar si un estilo de vida sedentariomodifica estas variaciones. Metodología: La condición física de 182 sujetos (48hombres, 134 mujeres) con una media de edad de 82,3 ±2,3 años se evaluó mediante 8 test (adaptados de las bate-rías “Senior Fitness Test” y “Eurofit”). Se realizó un aná-lisis de medidas repetidas entre los dos periodos de eva-luación y para ver las diferencias de condición física entrelos sujetos considerados sedentarios (permanecían senta-dos = 4 horas/día) y no sedentarios (permanecían senta-dos < 4 horas/día) Resultados: Entre las dos evaluaciones encontramos undescenso significativo en los test de agilidad (p 4 horas/día sufrieron un descen-so de la agilidad (p < 0,05). Se produjo una pérdida de ve-locidad y resistencia tanto en sedentarios como en no se-dentarios (p < 0,05). Conclusión: En dos años de seguimiento, se producencambios negativos en el nivel de condición física en perso-nas octogenarias. Periodos prolongados de sedestación setraducen en una pérdida de agilidad. La velocidad de lamarcha y resistencia parecen ser los componentes de lacondición física más afectados por el proceso de envejeci-miento en este grupo poblacional y su pérdida no vienedeterminada por las horas diarias de sedestación. Objective: The aim of this study was to determine the changes in physical fitness over two years of following up in octogenarian people and to check whether a sedentary lifestyle modify these variations. Methods: Physical fitness of 182 subject (48 men, 134 women)with a mean age of 82,3 ± 2,3 years were evaluated using 8 different tests. A repeated measures analysis was carried out to see the differences between the two evaluation periods and to see the physical fitness differences between sedentary people (sit = 4 hours/day)and non sedentary people (sit 4 hours/day there was a decrease in the walking speed test between the two evaluations (p < 0.05). Moreover, there was a decrease of walking speed and endurance between the two evaluation periods in both sedentary and nonsedentary people (p < 0.05). Conclusion: In two years of following up, there are adverse changes in the level of physical fitness in octogenarians. Long periods of sitting time may translate into a loss of agility. Walking speed and endurance seem to be the components of physical fitness more affected by the ageing process in this population; and this loss is not determined by the hours of sitting per day

Dataset of manually measured QT intervals in the electrocardiogram

BACKGROUND: The QT interval and the QT dispersion are currently a subject of considerable interest. Cardiac repolarization delay is known to favor the development of arrhythmias. The QT dispersion, defined as the difference between the longest and the shortest QT intervals or as the standard deviation of the QT duration in the 12-lead ECG is assumed to be reliable predictor of cardiovascular mortality. The seventh annual PhysioNet/Computers in Cardiology Challenge, 2006 addresses a question of high clinical interest: Can the QT interval be measured by fully automated methods with accuracy acceptable for clinical evaluations? METHOD: The PTB Diagnostic ECG Database was given to 4 cardiologists and 1 biomedical engineer for manual marking of QRS onsets and T-wave ends in 458 recordings. Each recording consisted of one selected beat in lead II, chosen visually to have minimum baseline shift, noise, and artifact. In cases where no T wave could be observed or its amplitude was very small, the referees were instructed to mark a 'group-T-wave end' taking into consideration leads with better manifested T wave. A modified Delphi approach was used, which included up to three rounds of measurements to obtain results closer to the median. RESULTS: A total amount of 2*5*548 Q-onsets and T-wave ends were manually marked during round 1. To obtain closer to the median results, 8.58 % of Q-onsets and 3.21 % of the T-wave ends had to be reviewed during round 2, and 1.50 % Q-onsets and 1.17 % T-wave ends in round 3. The mean and standard deviation of the differences between the values of the referees and the median after round 3 were 2.43 ± 0.96 ms for the Q-onset, and 7.43 ± 3.44 ms for the T-wave end. CONCLUSION: A fully accessible, on the Internet, dataset of manually measured Q-onsets and T-wave ends was created and presented in additional file: 1 (Table 4) with this article. Thus, an available standard can be used for the development of automated methods for the detection of Q-onsets, T-wave ends and for QT interval measurements