IP6 and PF74 affect HIV-1 Capsid Stability through Modulation of Hexamer-Hexamer Tilt Angle Preference.

The HIV-1 capsid is an irregularly shaped complex of about 1200 protein chains containing the viral genome and several viral proteins. Together, these components are the key to unlocking passage into the nucleus, allowing for permanent integration of the viral genome into the host cell genome. Recent interest into the role of the capsid in viral replication has been driven by the approval of the first-in-class drug lenacapavir, which marks the first drug approved to target a non-enzymatic HIV-1 viral protein. In addition to lenacapavir, other small molecules such as the drug-like compound PF74, and the anionic sugar inositolhexakisphosphate (IP6), are known to impact capsid stability, and although this is widely accepted as a therapeutic effect, the mechanisms through which they do so remain unknown. In this study, we employed a systematic atomistic simulation approach to study the impact of molecules bound to hexamers at the central pore (IP6) and the FG-binding site (PF74) on capsid oligomer dynamics, compared to apo hexamers and pentamers. We found that neither small molecule had a sizeable impact on the free energy of binding of the interface between neighboring hexamers but that both had impacts on the free energy profiles of performing angular deformations to the pair of oligomers akin to the variations in curvature along the irregular surface of the capsid. The IP6 cofactor, on one hand, stabilizes a pair of neighboring hexamers in their flattest configurations, whereas without IP6, the hexamers prefer a high tilt angle between them. On the other hand, having PF74 bound introduces a strong preference for intermediate tilt angles. These results suggest that structural instability is a natural feature of the HIV-1 capsid which is modulated by molecules bound in either the central pore or the FG-binding site. Such modulators, despite sharing many of the same effects on non-bonded interactions at the various protein-protein interfaces, have decidedly different effects on the flexibility of the complex. This study provides a detailed model of the HIV-1 capsid and its interactions with small molecules, informing structure-based drug design, as well as experimental design and interpretation.

Clostridioides difficile Sporulation.

Some members of the Firmicutes phylum, including many members of the human gut microbiota, are able to differentiate a dormant and highly resistant cell type, the endospore (hereinafter spore for simplicity). Spore-formers can colonize virtually any habitat and, because of their resistance to a wide variety of physical and chemical insults, spores can remain viable in the environment for long periods of time. In the anaerobic enteric pathogen Clostridioides difficile the aetiologic agent is the oxygen-resistant spore, while the toxins produced by actively growing cells are the main cause of the disease symptoms. Here, we review the regulatory circuits that govern entry into sporulation. We also cover the role of spores in the infectious cycle of C. difficile in relation to spore structure and function and the main control points along spore morphogenesis.

[A global core outcome measurement set for snakebite clinical trials]. / Définition d'un jeu universel de critères de décision de base pour les essais cliniques sur les morsures de serpent.

Background: Snakebite clinical trials have often used heterogeneous outcome measures and there is an urgent need for standardisation. Method: A globally representative group of key stakeholders came together to reach consensus on a globally relevant set of core outcome measurements. Outcome domains and outcome measurement instruments were identified through searching the literature and a systematic review of snakebite clinical trials. Outcome domains were shortlisted by use of a questionnaire and consensus was reached among stakeholders and the patient group through facilitated discussions and voting. Results: Five universal core outcome measures should be included in all future snakebite clinical trials: mortality, WHO disability assessment scale, patient-specific functional scale, acute allergic reaction by Brown criteria, and serum sickness by formal criteria. Additional syndrome-specific core outcome measures should be used depending on the biting species. Conclusion: This core outcome measurement set provides global standardisation, supports the priorities of patients and clinicians, enables meta-analysis, and is appropriate for use in low-income and middle-income settings.

Reactive Docking: A Computational Method for High-Throughput Virtual Screenings of Reactive Species.

We describe the formalization of the reactive docking protocol, a method developed to model and predict reactions between small molecules and biological macromolecules. The method has been successfully used in a number of applications already, including recapitulating large proteomics data sets, performing structure-reactivity target optimizations, and prospective virtual screenings. By modeling a near-attack conformation-like state, no QM calculations are required to model the ligand and receptor geometries. Here, we present its generalization using a large data set containing more than 400 ligand-target complexes, 8 nucleophilic modifiable residue types, and more than 30 warheads. The method correctly predicts the modified residue in ∼85% of complexes and shows enrichments comparable to standard focused virtual screenings in ranking ligands. This performance supports this approach for the docking and screening of reactive ligands in virtual chemoproteomics and drug design campaigns.

The GH/IGF axis in the sea lamprey during metamorphosis and seawater acclimation.

How the growth hormone (GH)/insulin-like growth factor (IGF) system affects osmoregulation in basal vertebrates remains unknown. We examined changes in the expression of components of the GH/IGF axis and gill ion transporters during metamorphosis and following seawater (SW) exposure of sea lamprey. During metamorphosis, increases in gill nka and nkcc1 and salinity tolerance were accompanied by increases in pituitary gh, liver igf1, gill ghr and igf1, but not liver ghr. SW exposure of fully metamorphosed sea lamprey resulted in slight increases in plasma chloride concentrations after SW exposure, indicating a high level of SW tolerance, but no major changes in mRNA levels of gill ion transporters or components of the GH/IGF axis. Our results indicate that metamorphosis is a critical point in the lifecycle of sea lamprey for stimulation of the GH/IGF axis and is temporally associated with and likely promotes metamorphosis and SW tolerance.

Ringtail: A Python Tool for Efficient Management and Storage of Virtual Screening Results.

Virtual screening using molecular docking is now routinely used for the rapid evaluation of very large ligand libraries in early stage drug discovery. As the size of compound libraries which can feasibly be screened grows, so do the challenges in result management and storage. Here we introduce Ringtail, a new Python tool in the AutoDock Suite for efficient storage and analysis of virtual screening data based on portable SQLite databases. Ringtail is designed to work with AutoDock-GPU and AutoDock Vina out-of-the-box. Its modular design also allows for easy extension to support input file types from other docking software, different storage solutions, and incorporation into other applications. Ringtail's SQLite database output can dramatically reduce the required disk storage (36-46 fold) by selecting individual poses to store and by taking advantage of the relational database format. Filtering times are also dramatically reduced, requiring minutes to filter millions of ligands. Thus, Ringtail is a tool that can immediately integrate into existing virtual screening pipelines using AutoDock-GPU and Vina, and is scriptable and modifiable to fit specific user needs.

A global core outcome measurement set for snakebite clinical trials.

Snakebite clinical trials have often used heterogeneous outcome measures and there is an urgent need for standardisation. A globally representative group of key stakeholders came together to reach consensus on a globally relevant set of core outcome measurements. Outcome domains and outcome measurement instruments were identified through searching the literature and a systematic review of snakebite clinical trials. Outcome domains were shortlisted by use of a questionnaire and consensus was reached among stakeholders and the patient group through facilitated discussions and voting. Five universal core outcome measures should be included in all future snakebite clinical trials-mortality, WHO disability assessment scale, patient-specific functional scale, acute allergic reaction by Brown criteria, and serum sickness by formal criteria. Additional syndrome-specific core outcome measures should be used depending on the biting species. This core outcome measurement set provides global standardisation, supports the priorities of patients and clinicians, enables meta-analysis, and is appropriate for use in low-income and middle-income settings.

Promoção do sono e repouso da pessoa em situação crítica: intervenção de enfermagem especializada / Promoting sleep and rest for people in critical situations: specialized nursing intervention

Este relatório foi realizado no âmbito da Unidade Curricular Estágio com Relatório (UCER), inserida no 11º Curso de Mestrado na área de Especialização de Enfermagem à Pessoa em Situação Crítica (CMEEPSC), da Escola Superior de Enfermagem de Lisboa (ESEL). O ritmo circadiano representa um conjunto de fenómenos fisiológicos, característicos dos seres vivos, durante um determinado período (24 horas) e que acontecem de forma repetida. Como parte integrante deste ritmo, o sono e repouso são fatores essenciais à vida humana. Os distúrbios do sono constituem uma epidemia global que ameaça a saúde e qualidade de vida de cerca de 45% da população mundial. O sono é definido como um estado fisiologicamente reversível, tendo como características a redução da mobilidade e a diminuição de respostas a estímulos sensoriais. É um processo ativo e complexo, não apenas um mero estado inerte, pelo que requer qualidade e quantidade, inseridos num horário próprio. Aquando de um internamento hospitalar numa situação de doença crítica, esta vertente pode ver-se afetada na PSC, pelo que intervir sobre ela contribuirá não só para a sua recuperação, mas também para a prevenção de complicações no seu processo de doença. Gerindo os momentos diários de maior e menor estimulação com a ajuda dos profissionais de saúde, permitirá à PSC conservar a energia necessária para participar ativamente no seu próprio processo de recuperação. A vigilância torna-se um fator essencial neste processo, uma vez que permite a identificação dos sinais e sintomas clinicamente relevantes na privação do sono e repouso, a elaboração de intervenções adequadas aos grau de risco a que a PSC está sujeita, por parte desses mesmos sinais e sintomas, bem como a prontidão e eficiência nas intervenções, minimizando esses mesmos riscos e dando resposta aos fatores condicionantes do sono e repouso da PSC. Assim, de forma a aprofundar a importância e atualidade deste tema, bem como o desenvolvimento das minhas competências de mestre e especialista na área de enfermagem à pessoa em situação crítica, foram realizados estágios em Serviço de Urgência (SU) e Unidade de Cuidados Intensivos (UCI), no âmbito da Unidade Curricular Estágio com Relatório, onde procurei olhar o problema do ponto de vista da realidade atual vivida no nosso país. Foi também elaborada uma revisão integrativa da literatura sobre o tema, que juntamente com a experiência adquirida no percurso dos estágios, me permitiu elaborar este documento.

This report was conducted within the scope of the curricular unit Internship with Report, included in the 11th Master's Course in the area of specialization in nursing for the critically ill person of the Escola Superior de Enfermagem de Lisboa. The circadian rhythm represents a number of physiological phenomena that occur in every living creature on an everyday basis, repeatedly, during a 24-hour period. As an integrative part of this rhythm, sleep and respite are an essential part of life. Sleep deprivation is a global problem that affects the health and quality of life of 45% of the world population. Sleep is defined as a reversible physiological state, in which there is mobility reduction and slow response to sensorial stimuli. It is an active and complex process and not just an inert state, requiring quality and quantity, during a given time. To intervene in the promotion of sleep and respite in a critically ill person is to contribute in its recovery process as well as to prevent any further health complications. Managing external stimuli given by healthcare professionals, in order to adapt it to a particular time of the day, allows the critically ill person to preserve the necessary energy to actively participate in its own recovery care and process. In order for this to happen, nursing professional vigilance becomes an essential factor that allows the identification of clinically relevant signals and symptoms in sleep deprivation. This professional vigilance process allows the elaboration of nursing interventions that are adequate to the level of risk to which the critically ill person is exposed, as well as the readiness and efficiency of its actions in minimizing those signals and symptoms experienced by the critically ill person. Therefore, in order to deepen the importance of this matter I have completed an internship in both an emergency department and critical care unit, within the scope of the curricular unit Internship with Report, where I was able to evaluate the problem, given the practical context. These internships along with an integrative literature review about this topic, allowed the development of my specialist nursing competences, as well as to shed light on this matter by writing this document.

Discovery of prolactin-like in lamprey: Role in osmoregulation and new insight into the evolution of the growth hormone/prolactin family.

We used a representative of one of the oldest extant vertebrate lineages (jawless fish or agnathans) to investigate the early evolution and function of the growth hormone (GH)/prolactin (PRL) family. We identified a second member of the GH/PRL family in an agnathan, the sea lamprey (Petromyzon marinus). Structural, phylogenetic, and synteny analyses supported the identification of this hormone as prolactin-like (PRL-L), which has led to added insight into the evolution of the GH/PRL family. At least two ancestral genes were present in early vertebrates, which gave rise to distinct GH and PRL-L genes in lamprey. A series of gene duplications, gene losses, and chromosomal rearrangements account for the diversity of GH/PRL-family members in jawed vertebrates. Lamprey PRL-L is produced in the proximal pars distalis of the pituitary and is preferentially bound by the lamprey PRL receptor, whereas lamprey GH is preferentially bound by the lamprey GH receptor. Pituitary PRL-L messenger RNA (mRNA) levels were low in larvae, then increased significantly in mid-metamorphic transformers (stage 3); thereafter, levels subsided in final-stage transformers and metamorphosed juveniles. The abundance of PRL-L mRNA and immunoreactive protein increased in the pituitary of juveniles under hypoosmotic conditions, and treatment with PRL-L blocked seawater-associated inhibition of freshwater ion transporters. These findings clarify the origin and divergence of GH/PRL family genes in early vertebrates and reveal a function of PRL-L in osmoregulation of sea lamprey, comparable to a role of PRLs that is conserved in jawed vertebrates.

Performance evaluation of flexible macrocycle docking in AutoDock.

Macrocycles represent an important class of ligands, both in natural products and designed drugs. In drug design, macrocyclizations can impart specific ligand conformations and contribute to passive permeation by encouraging intramolecular H-bonds. AutoDock-GPU and Vina can model macrocyclic ligands flexibly, without requiring the enumeration of macrocyclic conformers before docking. Here, we characterize the performance of the method for handling macrocyclic compounds, which is implemented and the default behaviour for ligand preparation with our ligand preparation pipeline, Meeko. A pseudoatom is used to encode bond geometry and produce an anisotropic closure force for macrocyclic rings. This method is evaluated on a diverse set of small molecule and peptide macrocycles, ranging from 7- to 33-membered rings, showing little accuracy loss compared to rigid redocking of the X-ray macrocycle conformers. This suggests that for conformationally flexible macrocycles with unknown binding modes, this method can be effectively used to predict the macrocycle conformation.

Benchmarking the Performance of Irregular Computations in AutoDock-GPU Molecular Docking.

Irregular applications can be found in different scientific fields. In computer-aided drug design, molecular docking simulations play an important role in finding promising drug candidates. AutoDock is a software application widely used for predicting molecular interactions at close distances. It is characterized by irregular computations and long execution runtimes. In recent years, a hardware-accelerated version of AutoDock, called AutoDock-GPU, has been under active development. This work benchmarks the recent code and algorithmic enhancements incorporated into AutoDock-GPU. Particularly, we analyze the impact on execution runtime of techniques based on early termination. These enable AutoDock-GPU to explore the molecular space as necessary, while safely avoiding redundant computations. Our results indicate that it is possible to achieve average runtime reductions of 50% by using these techniques. Furthermore, a comprehensive literature review is also provided, where our work is compared to relevant approaches leveraging hardware acceleration for molecular docking.

Integrating Social Determinants in Decision-Making Processes for Health: Insights from Conceptual Frameworks-the 3-D Commission.

The inclusion of social determinants of health offers a more comprehensive lens to fully appreciate and effectively address health. However, decision-makers across sectors still struggle to appropriately recognise and act upon these determinants, as illustrated by the ongoing COVID-19 pandemic. Consequently, improving the health of populations remains challenging. This paper seeks to draw insights from the literature to better understand decision-making processes affecting health and the potential to integrate data on social determinants. We summarised commonly cited conceptual approaches across all stages of the policy process, from agenda-setting to evaluation. Nine conceptual approaches were identified, including two frameworks, two models and five theories. From across the selected literature, it became clear that the context, the actors and the type of the health issue are critical variables in decision-making for health, a process that by nature is a dynamic and adaptable one. The majority of these conceptual approaches implicitly suggest a possible role for data on social determinants of health in decision-making. We suggest two main avenues to make the link more explicit: the use of data in giving health problems the appropriate visibility and credibility they require and the use of social determinants of health as a broader framing to more effectively attract the attention of a diverse group of decision-makers with the power to allocate resources. Social determinants of health present opportunities for decision-making, which can target modifiable factors influencing health-i.e. interventions to improve or reduce risks to population health. Future work is needed to build on this review and propose an improved, people-centred and evidence-informed decision-making tool that strongly and explicitly integrates data on social determinants of health.

COVID 19 repercussions in ophthalmology: a narrative review.

BACKGROUND: The new coronavirus of 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally and has repercussions within ophthalmological care. It has caused ocular manifestations in some patients, which can spread through eye secretions. OBJECTIVES: The purpose of this review was to summarize the currently available evidence on COVID-19 with regard to its implications for ophthalmology. DESIGN AND SETTING: Narrative review developed by a research group at Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brazil, and at Ludwig-Maximilians-Universität, Munich, Germany. METHODS: We searched the literature on the repercussions of COVID-19 within ophthalmological care, using the MEDLINE and LILACS databases, with the keywords "COVID-19", "ophthalmology" and "coronavirus", from January 1, 2020, to March 27, 2021. Clinical trials, meta-analysis, randomized controlled trials, reviews and systematic reviews were identified. RESULTS: We retrieved 884 references, of which 42 were considered eligible for intensive review and critical analysis. Most of the studies selected reported the evidence regarding COVID-19 and its implications for ophthalmology. CONCLUSIONS: Knowledge of eye symptoms and ocular transmission of the virus remains incomplete. New clinical trials with larger numbers of patients may answer these questions in the future. Moreover, positively, implementation of innovative changes in medicine such as telemedicine and artificial intelligence may assist in diagnosing eye diseases and in training and education for students.

Improving Decision-Making for Population Health in Nonhealth Sectors in Urban Environments: the Example of the Transportation Sector in Three Megacities-the 3-D Commission.

Noncommunicable diseases (NCDs) represent a significant global public health burden. As more countries experience both epidemiologic transition and increasing urbanization, it is clear that we need approaches to mitigate the growing burden of NCDs. Large and growing urban environments play an important role in shaping risk factors that influence NCDs, pointing to the ineluctable need to engage sectors beyond the health sector in these settings if we are to improve health. By way of one example, the transportation sector plays a critical role in building and sustaining health outcomes in urban environments in general and in megacities in particular. We conducted a qualitative comparative case study design. We compared Bus Rapid Transit (BRT) policies in 3 megacities-Lagos (Africa), Bogotá (South America), and Beijing (Asia). We examined the extent to which data on the social determinants of health, equity considerations, and multisectoral approaches were incorporated into local politics and the decision-making processes surrounding BRT. We found that all three megacities paid inadequate attention to health in their agenda-setting, despite having considerable healthy transportation policies in principle. BRT system policies have the opportunity to improve lifestyle choices for NCDs through a focus on safe, affordable, and effective forms of transportation. There are opportunities to improve decision-making for health by involving more available data for health, building on existing infrastructures, building stronger political leadership and commitments, and establishing formal frameworks to improve multisectoral collaborations within megacities. Future research will benefit from addressing the political and bureaucratic processes of using health data when designing public transportation services, the political and social obstacles involved, and the cross-national lessons that can be learned from other megacities.

AutoDock Vina 1.2.0: New Docking Methods, Expanded Force Field, and Python Bindings.

AutoDock Vina is arguably one of the fastest and most widely used open-source programs for molecular docking. However, compared to other programs in the AutoDock Suite, it lacks support for modeling specific features such as macrocycles or explicit water molecules. Here, we describe the implementation of this functionality in AutoDock Vina 1.2.0. Additionally, AutoDock Vina 1.2.0 supports the AutoDock4.2 scoring function, simultaneous docking of multiple ligands, and a batch mode for docking a large number of ligands. Furthermore, we implemented Python bindings to facilitate scripting and the development of docking workflows. This work is an effort toward the unification of the features of the AutoDock4 and AutoDock Vina programs. The source code is available at https://github.com/ccsb-scripps/AutoDock-Vina.