Natural compound plumbagin based inhibition of hIAPP revealed by Markov state models based on MD data along with experimental validations.

Human islet amyloid polypeptide (amylin or hIAPP) is a 37 residue hormone co-secreted with insulin from ß cells of the pancreas. In patients suffering from type-2 diabetes, amylin self-assembles into amyloid fibrils, ultimately leading to the death of the pancreatic cells. However, a research gap exists in preventing and treating such amyloidosis. Plumbagin, a natural compound, has previously been demonstrated to have inhibitory potential against insulin amyloidosis. Our investigation unveils collapsible regions within hIAPP that, upon collapse, facilitates hydrophobic and pi-pi interactions, ultimately leading to aggregation. Intriguingly plumbagin exhibits the ability to bind these specific collapsible regions, thereby impeding the aforementioned interactions that would otherwise drive hIAPP aggregation. We have used atomistic molecular dynamics approach to determine secondary structural changes. MSM shows metastable states forming native like hIAPP structure in presence of PGN. Our in silico results concur with in vitro results. The ThT assay revealed a striking 50% decrease in fluorescence intensity at a 1:1 ratio of hIAPP to Plumbagin. This finding suggests a significant inhibition of amyloid fibril formation by plumbagin, as ThT fluorescence directly correlates with the presence of these fibrils. Further TEM images revealed disappearance of hIAPP fibrils in plumbagin pre-treated hIAPP samples. Also, we have shown that plumbagin disrupts the intermolecular hydrogen bonding in hIAPP fibrils leading to an increase in the average beta strand spacing, thereby causing disaggregation of pre-formed fibrils demonstrating overall disruption of the aggregation machinery of hIAPP. Our work is the first to report a detailed atomistic simulation of 22 µs for hIAPP. Overall, our studies put plumbagin as a potential candidate for both preventive and therapeutic candidate for hIAPP amyloidosis.

Neural correlates of metacognition: Disentangling the brain circuits underlying prospective and retrospective second-order judgments through noninvasive brain stimulation.

Metacognition encompasses the capability to monitor and control one's cognitive processes, with metamemory and metadecision configuring among the most studied higher order functions. Although imaging experiments evaluated the role of disparate brain regions, neural substrates of metacognitive judgments remain undetermined. The aim of this systematic review is to summarize and discuss the available evidence concerning the neural bases of metacognition which has been collected by assessing the effects of noninvasive brain stimulation (NIBS) on human subjects' metacognitive capacities. Based on such literature analysis, our goal is, at first, to verify whether prospective and retrospective second-order judgments are localized within separate brain circuits and, subsequently, to provide compelling clues useful for identifying new targets for future NIBS studies. The search was conducted following the preferred reporting items for systematic reviews and meta-analyses guidelines among PubMed, PsycINFO, PsycARTICLES, PSYNDEX, MEDLINE, and ERIC databases. Overall, 25 studies met the eligibility criteria, yielding a total of 36 experiments employing transcranial magnetic stimulation and 16 ones making use of transcranial electrical stimulation techniques, including transcranial direct current stimulation and transcranial alternating current stimulation. Importantly, we found that both perspective and retrospective judgments about both memory and perceptual decision-making performances depend on the activation of the anterior and lateral portions of the prefrontal cortex, as well as on the activity of more caudal regions such as the premotor cortex and the precuneus. Combining this evidence with results from previous imaging and lesion studies, we advance ventromedial prefrontal cortex as a promising target for future NIBS studies.

The role of light emitting diode in wound healing: A systematic review of experimental studies.

Wounds represent a growing global issue demanding increased attention. To expedite wound healing, technologies are under development, and light emitting diode (LED) devices of varying wavelengths are being explored for their stimulating influence on the healing process. This article presents a systematic literature review aiming to compile, organize, and analyze the impacts of LED devices on wound healing. This review is registered on the PROSPERO platform [CRD42023403870]. Two blinded authors conducted searches in the Pubmed, Web of Science, Scopus, Embase, and ScienceDirect databases. In vitro and in vivo experimental studies assessing LED utilization in the wound healing process were included. The search yielded 1010 studies, of which 27 were included in the review. It was identified that LED stimulates different healing pathways, promoting enhanced cell proliferation and migration, angiogenesis stimulation, increased collagen deposition, and modulation of the inflammatory response. Thus, it can be concluded that the LED stimulates cellular and molecular processes contingent on the utilized parameters. The effects depend on the standards used. Cell migration and proliferation were better influenced by green and red LED. The extracellular matrix components and angiogenesis were regulated by all wavelengths and the modulation of inflammation was mediated by green, red, and infrared LEDs.

The advancement of artificial intelligence in biomedical research and health innovation: challenges and opportunities in emerging economies.

The advancement of artificial intelligence (AI), algorithm optimization and high-throughput experiments has enabled scientists to accelerate the discovery of new chemicals and materials with unprecedented efficiency, resilience and precision. Over the recent years, the so-called autonomous experimentation (AE) systems are featured as key AI innovation to enhance and accelerate research and development (R&D). Also known as self-driving laboratories or materials acceleration platforms, AE systems are digital platforms capable of running a large number of experiments autonomously. Those systems are rapidly impacting biomedical research and clinical innovation, in areas such as drug discovery, nanomedicine, precision oncology, and others. As it is expected that AE will impact healthcare innovation from local to global levels, its implications for science and technology in emerging economies should be examined. By examining the increasing relevance of AE in contemporary R&D activities, this article aims to explore the advancement of artificial intelligence in biomedical research and health innovation, highlighting its implications, challenges and opportunities in emerging economies. AE presents an opportunity for stakeholders from emerging economies to co-produce the global knowledge landscape of AI in health. However, asymmetries in R&D capabilities should be acknowledged since emerging economies suffers from inadequacies and discontinuities in resources and funding. The establishment of decentralized AE infrastructures could support stakeholders to overcome local restrictions and opens venues for more culturally diverse, equitable, and trustworthy development of AI in health-related R&D through meaningful partnerships and engagement. Collaborations with innovators from emerging economies could facilitate anticipation of fiscal pressures in science and technology policies, obsolescence of knowledge infrastructures, ethical and regulatory policy lag, and other issues present in the Global South. Also, improving cultural and geographical representativeness of AE contributes to foster the diffusion and acceptance of AI in health-related R&D worldwide. Institutional preparedness is critical and could enable stakeholders to navigate opportunities of AI in biomedical research and health innovation in the coming years.

Gain-of-function research and model organisms in biology.

So-called 'gain-of-function' (GOF) research is virological research that results in a virus substantially more virulent or transmissible than its wild antecedent. GOF research has been subject to ethical analysis in the past, but the methods of GOF research have to date been underexamined by philosophers in these analyses. Here, we examine the typical animal used in influenza GOF experiments, the ferret, and show how despite its longstanding use, it does not easily satisfy the desirable criteria for an animal model We then discuss the limitations of the ferret model, and how those epistemic limitations bear on ethical and policy questions around the risks and benefits of GOF research. We conclude with a reflection on how philosophy of science can contribute to ethical and policy debates around the risks, benefits and relative priority of life sciences research.

Effect of no-flow period on the vasopressor effect of initial epinephrine administration in cardiac arrest.

OBJECTIVES: Whether a longer no-flow (NF) interval affects the magnitude of response to epinephrine in the resuscitation has not been well studied. Therefore, this study aimed to evaluate the effect of NF interval on the vasopressor effect of initial epinephrine administration in a porcine model. METHODS: We enrolled 20 pigs from two randomized porcine experimental studies using a ventricular fibrillation (VF) cardiac arrest model. The first experiment subjects were resuscitated after 4 min of NF (Short NF group), followed by three cycles (6 min) of chest compression using a mechanical cardiopulmonary resuscitation device before epinephrine administration. Second experiment subjects received 6 min of NF (Long NF group), two cycles (4 min) of chest compressions, and administration of epinephrine. Defibrillation for VF was delivered 8 and 10 min after VF induction in the Short NF and Long NF groups, respectively. The mean arterial pressure (MAP) and cerebral perfusion pressure (CePP) in the 2-min resuscitation period after epinephrine administration were compared between the study groups using the Wilcoxon rank-sum test. The mean differences in the parameters between phases were also compared. RESULTS: Seven pigs in the Short NF group and 13 pigs in the Long NF group were included in the analysis. All 2-min resuscitation phases from 6 to 16 min after VF induction were compared between the study groups. The Short NF group showed higher MAP and CePP in all phases (p < 0.01). Change of mean MAP after the epinephrine administration was significantly different between the study groups: mean difference (95% confidence interval) of 16.6 (15.8-17.4) mmHg in the Short NF group and 4.2 (3.9-4.5) mmHg in the Long NF group. CONCLUSION: In the porcine VF cardiac arrest model, 6 min of NF before resuscitation may affect the vasopressor effect of the initial epinephrine administered compared to 4 min of NF. A short NF may play a role in maximizing the effect of epinephrine in advanced cardiovascular life support.

The End of Personhood.

The concept of personhood has been central to bioethics debates about abortion, the treatment of patients in a vegetative or minimally conscious states, as well as patients with advanced dementia. More recently, the concept has been employed to think about new questions related to human-brain organoids, artificial intelligence, uploaded minds, human-animal chimeras, and human embryos, to name a few. A common move has been to ask what these entities have in common with persons (in the normative sense), and then draw conclusions about what we do (or do not) owe them. This paper argues that at best the concept of "personhood" is unhelpful to much of bioethics today and at worst it is harmful and pernicious. I suggest that we (bioethicists) stop using the concept of personhood and instead ask normative questions more directly (e.g., how ought we to treat this being and why?) and use other philosophical concepts (e.g., interests, sentience, recognition respect) to help us answer them. It is time for bioethics to end talk about personhood.

Confidence intervals for policy evaluation in adaptive experiments.

Adaptive experimental designs can dramatically improve efficiency in randomized trials. But with adaptively collected data, common estimators based on sample means and inverse propensity-weighted means can be biased or heavy-tailed. This poses statistical challenges, in particular when the experimenter would like to test hypotheses about parameters that were not targeted by the data-collection mechanism. In this paper, we present a class of test statistics that can handle these challenges. Our approach is to adaptively reweight the terms of an augmented inverse propensity-weighting estimator to control the contribution of each term to the estimator's variance. This scheme reduces overall variance and yields an asymptotically normal test statistic. We validate the accuracy of the resulting estimates and their CIs in numerical experiments and show that our methods compare favorably to existing alternatives in terms of mean squared error, coverage, and CI size.

High-Throughput Screening of Streptavidin-Binding Proteins in Self-Assembled Solid Films for Directed Evolution of Materials.

Evolution has shaped the development of proteins with an incredible diversity of properties. Incorporating proteins into materials is desirable for applications including biosensing; however, high-throughput selection techniques for screening protein libraries in materials contexts is lacking. In this work, a high-throughput platform to assess the binding affinity for ordered sensing proteins was established. A library of fusion proteins, consisting of an elastin-like polypeptide block, one of 22 variants of rcSso7d, and a coiled-coil order-directing sequence, was generated. All selected variants had high binding in films, likely due to the similarity of the assay to magnetic bead sorting used for initial selection, while solution binding was more variable. From these results, both the assembly of the fusion proteins in their operating state and the functionality of the binding protein are key factors in the biosensing performance. Thus, the integration of directed evolution with assembled systems is necessary to the design of better materials.

Online false discovery rate control for LORD++ and SAFFRON under positive, local dependence.

Online testing procedures assume that hypotheses are observed in sequence, and allow the significance thresholds for upcoming tests to depend on the test statistics observed so far. Some of the most popular online methods include alpha investing, LORD++, and SAFFRON. These three methods have been shown to provide online control of the "modified" false discovery rate (mFDR) under a condition known as CS. However, to our knowledge, LORD++ and SAFFRON have only been shown to control the traditional false discovery rate (FDR) under an independence condition on the test statistics. Our work bolsters these results by showing that SAFFRON and LORD++ additionally ensure online control of the FDR under a "local" form of nonnegative dependence. Further, FDR control is maintained under certain types of adaptive stopping rules, such as stopping after a certain number of rejections have been observed. Because alpha investing can be recovered as a special case of the SAFFRON framework, our results immediately apply to alpha investing as well. In the process of deriving these results, we also formally characterize how the conditional super-uniformity assumption implicitly limits the allowed p-value dependencies. This implicit limitation is important not only to our proposed FDR result, but also to many existing mFDR results.

The Numbers of Animals Used in Mexico for Scientific and Educational Purposes.

In Mexico, there are no official public and reliably reported data on the total number and species of non-human animals used for scientific purposes. The aim of the current study was to calculate the total numbers of animals used for scientific and educational purposes in Mexico, from January 2015 to October 2021, based on data requested from the National Institute of Transparency, Access to Information and Protection of Personal Data (INAI, in Spanish). In this period, authorised laboratory animal facilities reported the use of 5,437,263 animals for scientific and educational purposes. However, these data should be viewed with caution, since there is no official register of all Mexican institutions that use animals for these purposes. The use of various species of different taxonomic groups was reported, including mammals, birds, reptiles, amphibians, fish and invertebrates. The main scientific purposes of this animal use were: technological development; innovation; laboratory testing; production of biologicals; quality control; diagnostic purposes; basic and applied research; and education. A robust system for the licensing and approval of animal use, as well as a means to ensure compliance with the relevant regulations, are both urgently required. In addition, in order to regulate animal use, monitor animal care and protect their welfare, the creation of a publicly accessible national database that records the number and species of the animals used is imperative.

A Novel Minimally Invasive Surgically Induced Skeletal Muscle Injury Model in Sheep.

Sports-related muscle injuries account for 10-55% of all injuries, which is a growing concern, especially given the aging world population. To evaluate the process of skeletal muscle injury and compare it with muscle lesions observed in humans, we developed a novel in vivo model in sheep. In this model, muscle injury was induced by an ultrasound-guided transverse biopsy at the myotendinous junction of the medial gastrocnemius muscle. Twelve male sheep were examined at 3, 7, 14, and 28 days post-injury. Histological, immunofluorescence, and MRI analyses indicate that our sheep model could resemble key human clinicopathological features. Statistically significant differences (p < 0.05) were observed in collagen I, dMHC, α-SMA, and CD68 immunohistochemical detection when comparing injured and healthy muscles. The injured gastrocnemius muscle exhibited elevated levels of type I collagen, infiltration of CD68(+) macrophages, angiogenesis, and the emergence of newly regenerated dMHC(+) myofibers, which persisted for up to 4 weeks post-injury. Similarly, the progression of muscle injury in the sheep model was assessed using advanced clinical 3 T MRI and compared with MRI scans from human patients. The data indicate that the sheep muscle injury model presents features similar to those observed in human skeletal muscle injuries. This makes it a valuable large animal model for studying muscle injuries and developing novel therapeutic strategies.

Assessing two methods of webcam-based eye-tracking for child language research.

We assess the feasibility of conducting web-based eye-tracking experiments with children using two methods of webcam-based eye-tracking: automatic gaze estimation with the WebGazer.js algorithm and hand annotation of gaze direction from recorded webcam videos. Experiment 1 directly compares the two methods in a visual-world language task with five to six year-old children. Experiment 2 more precisely investigates WebGazer.js' spatiotemporal resolution with four to twelve year-old children in a visual-fixation task. We find that it is possible to conduct web-based eye-tracking experiments with children in both supervised (Experiment 1) and unsupervised (Experiment 2) settings - however, the webcam eye-tracking methods differ in their sensitivity and accuracy. Webcam video annotation is well-suited to detecting fine-grained looking effects relevant to child language researchers. In contrast, WebGazer.js gaze estimates appear noisier and less temporally precise. We discuss the advantages and disadvantages of each method and provide recommendations for researchers conducting child eye-tracking studies online.

Speech production and perception data collection in R: A tutorial for web-based methods using speechcollectr.

This tutorial is designed for speech scientists familiar with the R programming language who wish to construct experiment interfaces in R. We begin by discussing some of the benefits of building experiment interfaces in R-including R's existing tools for speech data analysis, platform independence, suitability for web-based testing, and the fact that R is open source. We explain basic concepts of reactive programming in R, and we apply these principles by detailing the development of two sample experiments. The first of these experiments comprises a speech production task in which participants are asked to read words with different emotions. The second sample experiment involves a speech perception task, in which participants listen to recorded speech and identify the emotion the talker expressed with forced-choice questions and confidence ratings. Throughout this tutorial, we introduce the new R package speechcollectr, which provides functions uniquely suited to web-based speech data collection. The package streamlines the code required for speech experiments by providing functions for common tasks like documenting participant consent, collecting participant demographic information, recording audio, checking the adequacy of a participant's microphone or headphones, and presenting audio stimuli. Finally, we describe some of the difficulties of remote speech data collection, along with the solutions we have incorporated into speechcollectr to meet these challenges.

Indignity of Nazi data: reflections on the utilization of illicit research.

Human rights may feel self-apparent to us, but less than 80 years ago, one of the most advanced countries at the time acted based on an utterly contrary ideology. The view of social Darwinism that abandoned the idea of the intrinsic value of human lives instead argued that oppression of the inferior is not only inevitable but desirable. One of the many catastrophic outcomes is the medical data obtained from inhuman experiments at concentration camps. Ethical uncertainty over whether the resulting insights should be a part of the medical literature provides a chance to consider the seemingly irreplaceable social construct of human dignity. Would any medical benefit justify the utilization of this illicit data? Would utilization even qualify as an insult to the dignity of the exploited subjects, or is this a question about intersubjective meaning? This work discusses the wisdom in blind adherence to human dignity, the possibility of retrospective insults, moral complicity, contrary viewpoints, and possible resolutions.

[Exavir: Implementation and evaluation of experimental pharmacology skills acquisition by pharmacy students]. / Exavir : mise en place et évaluation de l'acquisition de compétences en pharmacologie expérimentale par des étudiants en pharmacie.

With the evolution of European and French regulations on animal experimentation in higher education, taking greater account of animal welfare, the University of Angers has developed a virtual animal experimentation software named Exavir. Used for practical work (PW) in physiology, pharmacology and toxicology in the Health, Sciences, and engineering curricula, Exavir can be used to simulate various experiments for teaching purposes, in vivo or ex vivo. Thanks to an original approach integrating serious games with different scenarios, students gain autonomy and become directly involved in their learning. In addition, Exavir's collaborative and participative development approach fosters inter-university partnerships and the emergence of innovative teaching methods. A hybrid pilot study carried out on a sample of 22 students in the Pharmacy Department of the Faculty of Health showed that Exavir improved students' acquisition of teaching skills in both physiology and pharmacology, compared with practical work only based on animal organs. These encouraging results demonstrate for the first time the pedagogical advantages of Exavir and confirm the interest in developing such a platform. In this context, it appears that Exavir also opens up the possibility of adapting the practical work offered within universities, and thus responding to the changing ethical issues of the coming decades.

Accelerating the Discovery of Oxygen Reduction Electrocatalysts: High-Throughput Screening of Element Combinations in Pt-Based High-Entropy Alloys.

The vast number of element combinations and the explosive growth of composition space pose significant challenges to the development of high-entropy alloys (HEAs). Here, we propose a procedural research method aimed at accelerating the discovery of efficient electrocatalysts for oxygen reduction reaction (ORR) based on Pt-based quinary HEAs. The method begins with an element library provided by a large language model (LLM), combined with microscale precursor printing and pulse high-temperature synthesis techniques to prepare multi-element combination HEA array in one step. Through high-throughput measurement using scanning electrochemical cell microscopy (SECCM), precise identification of highly active HEA element combinations and exploration of composition space for a specific combination are achieved. Advantageous element combinations are further validated in practical electrocatalytic evaluations. The contributions of individual element sites and the synergistic effects among elements of such HEAs in enhancing reaction activity are elucidated via density functional theory (DFT) calculations. This method integrates high-throughput experiments, practical catalyst validation, and DFT calculations, providing a new pathway for accelerating the discovery of efficient multi-element materials in the field of energy catalysis.

Experimentation in cosmology: Intervening on the whole universe.

There are many arguments against the possibility of experimenting on the whole universe. This system seems to be too big to be manipulated, it exists in only one exemplar and its evolution is a non-repeatable process. In this paper, I claim that we can nonetheless talk about experimentation in cosmology if we use Woodward's non-anthropocentric notion of intervention. However, Woodward and other interventionists argued that an intervention was necessarily an exogenous causal process and thus that no intervention on a closed system such as the universe was possible. I discuss their argument and I determine the conditions under which a consistent notion of endogenous intervention on the universe can be defined. Then, I show that there is at least one cosmic phenomenon satisfying these conditions: the photon decoupling. Finally, I draw some conclusions from this analysis regarding a realist approach of cosmology.

[From immersion to inclusion, a learning experience]. / De l'immersion à l'inclusion, une expérience apprenante.

As part of their training, volunteer nursing students from the Gers healthcare training institute were invited to take part in a sports exchange with a handibasket team. The main aim of the project was to change their perceptions of disability. Here, four of the students share their experiences and the benefits of the experience.

Smartphone-based ear-electroencephalography to study sound processing in everyday life.

In everyday life, people differ in their sound perception and thus sound processing. Some people may be distracted by construction noise, while others do not even notice. With smartphone-based mobile ear-electroencephalography (ear-EEG), we can measure and quantify sound processing in everyday life by analysing presented sounds and also naturally occurring ones. Twenty-four participants completed four controlled conditions in the lab (1 h) and one condition in the office (3 h). All conditions used the same paired-click stimuli. In the lab, participants listened to click tones under four different instructions: no task towards the sounds, reading a newspaper article, listening to an audio article or counting a rare deviant sound. In the office recording, participants followed daily activities while they were sporadically presented with clicks, without any further instruction. In the beyond-the-lab condition, in addition to the presented sounds, environmental sounds were recorded as acoustic features (i.e., loudness, power spectral density and sounds onsets). We found task-dependent differences in the auditory event-related potentials (ERPs) to the presented click sounds in all lab conditions, which underline that neural processes related to auditory attention can be differentiated with ear-EEG. In the beyond-the-lab condition, we found ERPs comparable to some of the lab conditions. The N1 amplitude to the click sounds beyond the lab was dependent on the background noise, probably due to energetic masking. Contrary to our expectation, we did not find a clear ERP in response to the environmental sounds. Overall, we showed that smartphone-based ear-EEG can be used to study sound processing of well defined-stimuli in everyday life.