Rapid 40S scanning and its regulation by mRNA structure during eukaryotic translation initiation.

How the eukaryotic 43S preinitiation complex scans along the 5' untranslated region (5' UTR) of a capped mRNA to locate the correct start codon remains elusive. Here, we directly track yeast 43S-mRNA binding, scanning, and 60S subunit joining by real-time single-molecule fluorescence spectroscopy. 43S engagement with mRNA occurs through a slow, ATP-dependent process driven by multiple initiation factors including the helicase eIF4A. Once engaged, 43S scanning occurs rapidly and directionally at ∼100 nucleotides per second, independent of multiple cycles of ATP hydrolysis by RNA helicases post ribosomal loading. Scanning ribosomes can proceed through RNA secondary structures, but 5' UTR hairpin sequences near start codons drive scanning ribosomes at start codons backward in the 5' direction, requiring rescanning to arrive once more at a start codon. Direct observation of scanning ribosomes provides a mechanistic framework for translational regulation by 5' UTR structures and upstream near-cognate start codons.

eIF5B and eIF1A reorient initiator tRNA to allow ribosomal subunit joining.

Translation initiation defines the identity and quantity of a synthesized protein. The process is dysregulated in many human diseases1,2. A key commitment step is when the ribosomal subunits join at a translation start site on a messenger RNA to form a functional ribosome. Here, we combined single-molecule spectroscopy and structural methods using an in vitro reconstituted system to examine how the human ribosomal subunits join. Single-molecule fluorescence revealed when the universally conserved eukaryotic initiation factors eIF1A and eIF5B associate with and depart from initiation complexes. Guided by single-molecule dynamics, we visualized initiation complexes that contained both eIF1A and eIF5B using single-particle cryo-electron microscopy. The resulting structure revealed how eukaryote-specific contacts between the two proteins remodel the initiation complex to orient the initiator aminoacyl-tRNA in a conformation compatible with ribosomal subunit joining. Collectively, our findings provide a quantitative and architectural framework for the molecular choreography orchestrated by eIF1A and eIF5B during translation initiation in humans.

Effect of paediatric early warning systems (PEWS) implementation on clinical deterioration event mortality among children with cancer in resource-limited hospitals in Latin America: a prospective, multicentre cohort study.

BACKGROUND: Paediatric early warning systems (PEWS) aid in the early identification of clinical deterioration events in children admitted to hospital. We aimed to investigate the effect of PEWS implementation on mortality due to clinical deterioration in children with cancer in 32 resource-limited hospitals across Latin America. METHODS: Proyecto Escala de Valoración de Alerta Temprana (Proyecto EVAT) is a quality improvement collaborative to implement PEWS in hospitals providing childhood cancer care. In this prospective, multicentre cohort study, centres joining Proyecto EVAT and completing PEWS implementation between April 1, 2017, and May 31, 2021, prospectively tracked clinical deterioration events and monthly inpatient-days in children admitted to hospital with cancer. De-identified registry data reported between April 17, 2017, and Nov 30, 2021, from all hospitals were included in analyses; children with limitations on escalation of care were excluded. The primary outcome was clinical deterioration event mortality. Incidence rate ratios (IRRs) were used to compare clinical deterioration event mortality before and after PEWS implementation; multivariable analyses assessed the correlation between clinical deterioration event mortality and centre characteristics. FINDINGS: Between April 1, 2017, and May 31, 2021, 32 paediatric oncology centres from 11 countries in Latin America successfully implemented PEWS through Proyecto EVAT; these centres documented 2020 clinical deterioration events in 1651 patients over 556 400 inpatient-days. Overall clinical deterioration event mortality was 32·9% (664 of 2020 events). The median age of patients with clinical deterioration events was 8·5 years (IQR 3·9-13·2), and 1095 (54·2%) of 2020 clinical deterioration events were reported in male patients; data on race or ethnicity were not collected. Data were reported per centre for a median of 12 months (IQR 10-13) before PEWS implementation and 18 months (16-18) after PEWS implementation. The mortality rate due to a clinical deterioration event was 1·33 events per 1000 patient-days before PEWS implementation and 1·09 events per 1000 patient-days after PEWS implementation (IRR 0·82 [95% CI 0·69-0·97]; p=0·021). In the multivariable analysis of centre characteristics, higher clinical deterioration event mortality rates before PEWS implementation (IRR 1·32 [95% CI 1·22-1·43]; p<0·0001), being a teaching hospital (1·18 [1·09-1·27]; p<0·0001), not having a separate paediatric haematology-oncology unit (1·38 [1·21-1·57]; p<0·0001), and having fewer PEWS omissions (0·95 [0·92-0·99]; p=0·0091) were associated with a greater reduction in clinical deterioration event mortality after PEWS implementation; no association was found with country income level (IRR 0·86 [95% CI 0·68-1·09]; p=0·22) or clinical deterioration event rates before PEWS implementation (1·04 [0·97-1·12]; p=0·29). INTERPRETATION: PEWS implementation was associated with reduced clinical deterioration event mortality in paediatric patients with cancer across 32 resource-limited hospitals in Latin America. These data support the use of PEWS as an effective evidence-based intervention to reduce disparities in global survival for children with cancer. FUNDING: American Lebanese Syrian Associated Charities, US National Institutes of Health, and Conquer Cancer Foundation. TRANSLATIONS: For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Courtship behavior in the knife livebearer Alfaro cultratus (Cyprinodontiformes: Poeciliidae).

The mating behavior of the knife livebearer Alfaro cultratus is described in detail. During "rubbing," the male swims to a position above the female and gently moves down repeatedly touching the dorsal part of female head with the pelvic fin tips. This courtship behavior constitutes the first report of a pelvic fin male-female contact during mating in poecilids. Based on preliminary evidence, I propose that a sensory bias mechanism could mediate the evolution of signal design/mate choice in this species, which should be tested in further studies.

Extracellular Vesicles and Their Zeta Potential as Future Markers Associated with Nutrition and Molecular Biomarkers in Breast Cancer.

A nutritional intervention promotes the loss of body and visceral fat while maintaining muscle mass in breast cancer patients. Extracellular vesicles (EVs) and their characteristics can be potential biomarkers of disease. Here, we explore the changes in the Zeta potential of EVs; the content of miRNA-30, miRNA-145, and miRNA-155; and their association with body composition and biomarkers of metabolic risk in breast cancer patients, before and 6 months after a nutritional intervention. Clinicopathological data (HER2neu, estrogen receptor, and Ki67), anthropometric and body composition data, and plasma samples were available from a previous study. Plasma EVs were isolated and characterized in 16 patients. The expression of miRNA-30, miRNA-145, and miRNA-155 was analyzed. The Zeta potential was associated with HER2neu (ß = 2.1; p = 0.00), Ki67 (ß = -1.39; p = 0.007), estrogen positive (ß = 1.57; p = 0.01), weight (ß = -0.09; p = 0.00), and visceral fat (ß = 0.004; p = 0.00). miRNA-30 was associated with LDL (ß = -0.012; p = 0.01) and HDL (ß = -0.02; p = 0.05). miRNA-155 was associated with visceral fat (ß = -0.0007; p = 0.05) and Ki67 (ß = -0.47; p = 0.04). Our results reveal significant associations between the expression of miRNA-30 and miRNA-155 and the Zeta potential of the EVs with biomarkers of metabolic risk and disease prognosis in women with breast cancer; particularly, the Zeta potential of EVs can be a new biomarker sensitive to changes in the nutritional status and breast cancer progression.

Model for regional collaboration: Successful strategy to implement a pediatric early warning system in 36 pediatric oncology centers in Latin America.

BACKGROUND: Pediatric early warning systems (PEWS) aid in the early identification of deterioration in hospitalized children with cancer; however, they are under-used in resource-limited settings. The authors use the knowledge-to-action framework to describe the implementation strategy for Proyecto Escala de Valoracion de Alerta Temprana (EVAT), a multicenter quality-improvement collaborative, to scale-up PEWS in pediatric oncology centers in Latin America. METHODS: Proyecto EVAT mentored participating centers through an adaptable implementation strategy to: (1) monitor clinical deterioration in children with cancer, (2) contextually adapt PEWS, (3) assess barriers to using PEWS, (4) pilot and implement PEWS, (5) monitor the use of PEWS, (6) evaluate outcomes, and (7) sustain PEWS. The implementation outcomes assessed included the quality of PEWS use, the time required for implementation, and global program impact. RESULTS: From April 2017 to October 2021, 36 diverse Proyecto EVAT hospitals from 13 countries in Latin America collectively managing more than 4100 annual new pediatric cancer diagnoses successfully implemented PEWS. The time to complete all program phases varied among centers, averaging 7 months (range, 3-13 months) from PEWS pilot to implementation completion. All centers ultimately implemented PEWS and maintained high-quality PEWS use for up to 18 months after implementation. Across the 36 centers, more than 11,100 clinicians were trained in PEWS, and more than 41,000 pediatric hospital admissions had PEWS used in their care. CONCLUSIONS: Evidence-based interventions like PEWS can be successfully scaled-up regionally basis using a systematic approach that includes a collaborative network, an adaptable implementation strategy, and regional mentorship. Lessons learned can guide future programs to promote the widespread adoption of effective interventions and reduce global disparities in childhood cancer outcomes. LAY SUMMARY: Pediatric early warning systems (PEWS) are clinical tools used to identify deterioration in hospitalized children with cancer; however, implementation challenges limit their use in resource-limited settings. Proyecto EVAT is a multicenter quality-improvement collaborative to implement PEWS in 36 pediatric oncology centers in Latin America. This is the first multicenter, multinational study reporting a successful implementation strategy (Proyecto EVAT) to regionally scale-up PEWS. The lessons learned from Proyecto EVAT can inform future programs to promote the adoption of clinical interventions to globally improve childhood cancer outcomes.

Effects of aversive conditioning on expression of physiological stress in honey bees (Apis mellifera).

Stress is defined as any deviation from an organism's baseline physiological levels. Therefore, introduction of new stimuli and information, such as in learning, can be defined as a stressor. A large body of research exists examining the role that stress plays in learning, but virtually none addresses whether or not learning itself is a measurable cause of stress. The current study used a wide variety of learning centric stress responses. Researchers examined changes in expression of ten stress and learning related genes in various physiological systems in domesticated honey bees (Apis mellifera) as a result of exposure to an aversive conditioning task. Gene expression was examined using quantitative real-time polymerase chain reaction following the learning task. Results indicate that learning affects expression of some stress related genes.

Genetic and ecomorphological divergence between sympatric Astyanax morphs from Central America.

Intraspecific ecological and morphological polymorphism can promote ecological speciation and the build-up of reproductive isolation. Here, we evaluate correlations among morphology, trophic ecology and genetic differentiation between two divergent morphs (elongate and deep-body) of the fish genus Astyanax in the San Juan River basin in Central America, to infer the putative evolutionary mechanism shaping this system. We collected the two morphs from three water bodies and analysed: (1) the correlation between body shape and the shape of the premaxilla, a relevant trophic morphological structure, (2) the trophic level and niche width of each morph, (3) the correspondence between trophic level and body and premaxillary shape, and (4) the genetic differentiation between morphs using mitochondrial and nuclear markers. We found a strong correlation between the body and premaxillary shape of the morphs. The elongate-body morph had a streamlined body, a premaxilla with acuter angles and a narrower ascending process, and a higher trophic level, characteristic of species with predatorial habits. By contrast, the deep-body morph had a higher body depth, a premaxilla with less acute angles and a broader trophic niche, suggesting generalist habits. Despite the strong correlation between morphological and ecological divergence, the morphs showed limited genetic differentiation, supporting the idea that morphs may be undergoing incipient ecological speciation, although alternative scenarios such as stable polymorphism or plasticity should also be considered. This study provides support for the role of ecological factors promoting diversification in both lake and stream-dwelling freshwater fish.

Behavioral flexibility in Wasmannia auropunctata (Hymenoptera: Formicidae).

Worker division of labor is a defining trait in social insects. Many species are characterized by having behavioral flexibility where workers perform non-typical tasks for their age depending on the colony's needs. Worker division of labor and behavioral flexibility were examined in the little fire ant Wasmannia auropunctata (Roger, 1863), for which age-related division of labor has been found. Young workers perform nursing duties which include tending of brood and queens, and colony defense, while older workers forage. When nurses were experimentally removed from the colony, foragers were observed carrying out nursing and colony defense duties, yet when foragers were removed nurses did not forage precociously. We also administered juvenile hormone analog, methoprene, to workers. When methoprene was applied, foragers increased their nursing and defense activities while nurses became mainly idle. The behavioral flexibility of foragers of the little fire ant may be evidence of an expansion of worker's repertoires as they age; older workers can perform tasks they have already done in their life while young individuals are not capable of performing tasks ahead of time. This may be an important adaptation associated with the success of this ant as an invasive species.

"Never sacrifice anything to laboratory work": The "physiological psychology" of Charles Richet (1875-1905).

Whilst best known as a Nobel laureate physiologist, Charles Robert Richet (1850-1935) was also a pioneer of scientific psychology. Starting in 1875 Richet had a leading role in the habilitation of hypnosis, in the institutionalization of psychology in France, and in the introduction of methodological innovations. Authoring several psychology books, Richet's works contributed to the recognition of the scientific nature of the discipline. This role is often underplayed by some historians and psychology textbooks in favor of his later position as a proponent of the controversial discipline he christened metapsychics in 1905, which today lies within the province of parapsychology. In this article, we show how his psychological approach guided by physiology, or physiological psychology, facilitated the reception of psychology. We hypothesize a strong continuity between his physiological psychology and his metapsychics, as he himself considered metapsychics as an advanced branch of physiology, and thus also an outpost of psychology.

Camille Flammarion on the powers of the soul; with an introduction by Carlos S.

There is a long conceptual tradition that interprets phenomena such as clairvoyance and apparitions as evidence for a spiritual component in human beings. Examples of this appear in the literatures of mesmerism, Spiritualism and psychical research. The purpose of this Classic Text is to present excerpts from a book by French astronomer Camille Flammarion touching on this perspective. They are selected from the introduction and conclusion of Flammarion's L'Inconnu: The Unknown (1900), a translation of L'Inconnu et les problèmes psychiques (1900), in which he published and commented on cases of apparitions and other phenomena he collected. In his view, these phenomena showed the existence of the soul. Similar beliefs regarding ideas of the nonphysical nature of human beings and psychic phenomena have continued to the present.

Development of a Fragment-Based Screening Assay for the Focal Adhesion Targeting Domain Using SPR and NMR.

The Focal Adhesion Targeting (FAT) domain of Focal Adhesion Kinase (FAK) is a promising drug target since FAK is overexpressed in many malignancies and promotes cancer cell metastasis. The FAT domain serves as a scaffolding protein, and its interaction with the protein paxillin localizes FAK to focal adhesions. Various studies have highlighted the importance of FAT-paxillin binding in tumor growth, cell invasion, and metastasis. Targeting this interaction through high-throughput screening (HTS) provides a challenge due to the large and complex binding interface. In this report, we describe a novel approach to targeting FAT through fragment-based drug discovery (FBDD). We developed two fragment-based screening assays-a primary SPR assay and a secondary heteronuclear single quantum coherence nuclear magnetic resonance (HSQC-NMR) assay. For SPR, we designed an AviTag construct, optimized SPR buffer conditions, and created mutant controls. For NMR, resonance backbone assignments of the human FAT domain were obtained for the HSQC assay. A 189-compound fragment library from Enamine was screened through our primary SPR assay to demonstrate the feasibility of a FAT-FBDD pipeline, with 19 initial hit compounds. A final total of 11 validated hits were identified after secondary screening on NMR. This screening pipeline is the first FBDD screen of the FAT domain reported and represents a valid method for further drug discovery efforts on this difficult target.

Jules Bernard Luys on magnetic pathology.

In the mesmeric movement, one of the phenomena cited to defend the existence of magnetic and nervous forces was the visual perception of them in the form of luminous emanations from people, or effluvia. This Classic Text is an 1892 article by French neurologist, Jules Bernard Luys (1828-97), about the observation of such effluvia by hypnotized individuals. Interestingly, the luminous phenomena perceived from mentally diseased individuals and from healthy ones had particular properties. Luys's interest in this and other unorthodox phenomena were consistent with ideas of animal magnetism in the late neo-mesmeric movement, as well as with some physicalistic conceptions of hypnosis and the nervous system held at the time.

A New Class of Metal-Cyclam-Based Zirconium Metal-Organic Frameworks for CO2 Adsorption and Chemical Fixation.

Metal-organic frameworks (MOFs) have shown great promise in catalysis, mainly due to their high content of active centers, large internal surface areas, tunable pore size, and versatile chemical functionalities. However, it is a challenge to rationally design and construct MOFs that can serve as highly stable and reusable heterogeneous catalysts. Here two new robust 3D porous metal-cyclam-based zirconium MOFs, denoted VPI-100 (Cu) and VPI-100 (Ni), have been prepared by a modulated synthetic strategy. The frameworks are assembled by eight-connected Zr6 clusters and metallocyclams as organic linkers. Importantly, the cyclam core has accessible axial coordination sites for guest interactions and maintains the electronic properties exhibited by the parent cyclam ring. The VPI-100 MOFs exhibit excellent chemical stability in various organic and aqueous solvents over a wide pH range and show high CO2 uptake capacity (up to ∼9.83 wt% adsorption at 273 K under 1 atm). Moreover, VPI-100 MOFs demonstrate some of the highest reported catalytic activity values (turnover frequency and conversion efficiency) among Zr-based MOFs for the chemical fixation of CO2 with epoxides, including sterically hindered epoxides. The MOFs, which bear dual catalytic sites (Zr and Cu/Ni), enable chemistry not possible with the cyclam ligand under the same conditions and can be used as recoverable stable heterogeneous catalysts without losing performance.

Final chapter, From India to the Planet Mars: A Study of a Case of Somnambulism with Glossolalia, by Théodore Flournoy (1900).

Among the many attempts to explain mediumship psychologically at the turn of the century were the efforts of Swiss psychologist Théodore Flournoy (1854-1920). In his well-known book Des Indes à la Planète Mars (1900), translated as From India to the Planet Mars (1900), Flournoy analysed the mediumistic productions of medium Hélène Smith (1861-1929), consisting of accounts of previous lives in France and in India, and material about planet Mars. Flournoy explained the phenomena as a function of cryptomnesia, suggestive influences, and subconscious creativity, analyses that influenced both psychology and psychical research. The purpose of this Classic Text is to reprint the conclusion of Flournoy's study, whose ideas were developed in the context of psychological attention to mediumship and secondary personalities.

Cesare Lombroso on mediumship and pathology.

During the nineteenth century and the first decade of the twentieth, students of pathology such as Cesare Lombroso (1835-1909), the author of the excerpt presented here, became involved in observing, investigating and theorizing about the phenomena of Spiritualism, and mediumship in particular. The Classic Text presented here consists of an excerpt from Lombroso's writings which focus on the Italian medium Eusapia Palladino (1854-1918), who greatly influenced Lombroso's beliefs. Lombroso illustrates neglected theoretical ideas combining the interaction of pathology and what seem to be real psychic phenomena that have not received much attention in historical studies.

'Report of the Committee on Mediumistic Phenomena', by William James (1886): With an introduction by.

Mediumship was a topic of great interest to some nineteenth-century students of mental phenomena. Together with the phenomena of hypnosis and other manifestations, mediumship was seen by many as a dissociative phenomenon. The purpose of this Classic Text is to present an excerpt of an article about the topic that William James (1842-1910) published in 1886 in the Proceedings of the American Society for Psychical Research about American medium Leonora E. Piper (1857-1950). The article, an indication of late nineteenth-century interactions between dissociation studies and psychical research, was the first report of research with Mrs Piper, a widely investigated medium of great importance for the development of mediumship studies. In addition to studying the case as a dissociative experience, James explored the possibility that Piper's mentation contained verifiable information suggestive of 'supernormal' knowledge. Consequently, James provides an example of a topic neglected in historical studies, the ideas of those who combined conventional dissociation studies with psychical research.

Joseph Maxwell on mediumistic personifications.

The study of mediumship received much impetus from the work of psychical researchers. This included ideas about the phenomena of personation, or changes in attitudes, dispositions and behaviours shown by some mediums that supposedly indicated discarnate action. The aim of this Classic Text is to reprint passages about this topic from the writings of French psychical researcher Joseph Maxwell (1858-1938), which were part of the contributions of some psychical researchers to reconceptualize the manifestations in psychological terms. Maxwell suggested these changes in mediums were a production of their subconscious mind. His ideas are a reflection of previous theorization about secondary personalities and a particular example of the contributions of psychical researchers to understand the psychology of mediumship.

Thermodynamic Study of CO2 Sorption by Polymorphic Microporous MOFs with Open Zn(II) Coordination Sites.

Two Zn-based metal organic frameworks have been prepared solvothermally, and their selectivity for CO2 adsorption was investigated. In both frameworks, the inorganic structural building unit is composed of Zn(II) bridged by the 2-carboxylate or 5-carboxylate pendants of 2,5-pyridine dicarboxylate (pydc) to form a 1D zigzag chain. The zigzag chains are linked by the bridging 2,5-carboxylates across the Zn ions to form 3D networks with formulas of Zn4(pydc)4(DMF)2·3DMF (1) and Zn2(pydc)2(DEF) (2). The framework (1) contains coordinated DMF as well as DMF solvates (DMF = N,N-dimethylformamide), while (2) contains coordinated DEF (DEF = N,N-diethylformamide). (1) displays a reversible type-I sorption isotherm for CO2 and N2 with BET surface areas of 196 and 319 m(2)/g, respectively. At low pressures, CO2 and N2 isotherms for (2) were not able to reach saturation, indicative of pore sizes too small for the gas molecules to penetrate. A solvent exchange to give (2)-MeOH allowed for increased CO2 and N2 adsorption onto the MOF surface with BET surface areas of 41 and 39 m(2)/g, respectively. The binding of CO2 into the framework of (1) was found to be exothermic with a zero coverage heat of adsorption, Qst(0), of −27.7 kJ/mol. The Qst(0) of (2) and (2)-MeOH were found to be −3 and −41 kJ/mol, respectively. The CO2/N2 selectivity for (1), calculated from the estimated KH at 296 K, was found to be 42. At pressures relevant to postcombustion capture, the selectivity was 14. The thermodynamic data are consistent with a mechanism of adsorption that involves CO2 binding to the unsaturated Zn(II) metal centers present in the crystal structures.

Outcomes of total hip arthroplasty in human immunodeficiency virus-positive patients.

Today, patients with human immunodeficiency virus (HIV) live long enough to develop chronic degenerative and HIV-associated joint disease. There is a growing population of patients infected with HIV who are candidates for total hip arthroplasty (THA). A total of 31 HIV-positive, non-hemophilic patients undergoing 41 THAs at our institution between 2000 and 2012 were identified. In-hospital medical complications were reported in 5 of 41 hips, all of which resolved prior to discharge. Deep infection developed in 1 of 41 hips and revision was required in 3 of 41 hips. These results suggest that low rates of complications and revision can be achieved in the HIV-positive, non-hemophilic population. We believe that with careful patient selection, THA may improve the quality of life in the HIV-positive population.